ES2727275T3 - Automatic portable injection device for controlled release of therapeutic agents - Google Patents

Abstract

An automatic portable injection device (100, 600, 1800, 2400, 2800, 4100, 5100) free of a battery to provide a subcutaneous injection of a therapeutic agent into a patient, the portable automatic injection device comprising: a housing (102 , 202, 635, 735, 1802, 2002, 2102, 2402, 5102, 5204, 5302, 5404, 5504) comprising a portion of contact with the patient that can be fixed to the patient; an injection assembly disposed mobilely in the housing containing a hypodermic injection needle (118, 218, 625, 725, 1206, 1306, 1812, 2008, 5202, 5304) for insertion into the patient, the injection assembly movable between a retracted position in which the injection needle does not protrude outside the housing and an extended position in which the injection needle protrudes outside the housing; a container (106, 206, 605, 705, 1102, 1202, 1302, 1400, 1606, 1706, 2004, 2506, 2804, 2902, 4104, 4602) provided in the housing to contain the therapeutic agent; a plunger (110, 210, 615, 715, 2408, 2508, 2802, 3916) disposed mobilely in the container to expel the therapeutic agent from the container in the injection assembly; a plunger drive mechanism (112, 212, 630, 730, 2406, 2510, 3900, 4000) to drive the plunger using a mechanical or hydraulic mechanism inside the vessel; a retraction activator (5312, 5314) sensitive to a change of state of the portable automatic injection device from an injection state to a post-injection state, in which the portable automatic injection device enters the post-injection state after the administration of a therapeutically effective dose of the therapeutic agent is completed and enters the post-injection state after the withdrawal of the portable automatic injection device from the patient before the end of the administration of the therapeutically effective dose of the therapeutic agent; and a retraction mechanism (4810) for automatically retracting the injection assembly from the extended position in the injection state to the retracted position in the post-injection state after activation by the retraction activator.

Description

DESCRIPTION

Automatic portable injection device for controlled release of therapeutic agents

State of the art

Automatic injection devices offer an alternative to manually operated syringes to administer therapeutic agents to patients' bodies and allow patients to self-administer injections. Automatic injection devices have been used to administer medications in emergency conditions, for example, administer epinephrine to counteract the effects of a severe allergic reaction. Automatic injection devices have also been described for use in administering antiarrhythmic medications and selective thrombolytic agents during myocardial infarction (see, for example, U.S. Patent Nos. 3,910,260; 4,004,577; 4,689. 042; 4,755,169; and 4,795,433). Various types of automatic injection devices are also described in, for example, US Pat. No. 3,941,130; 4,261,358; 5,085,642; 5,092,843; 5,102,393; 5,267,963; 6,149,626; 6,270,479; and 6,371,939; and international patent publication No. WO / 2008/005315.

Conventionally, an automatic injection device houses a syringe and, when actuated, causes the syringe to move forward and project a needle from the housing so that a therapeutic agent contained in the syringe is ejected into the skin of a patient. An automatic injection device typically includes a cap disposed within the syringe that, when operated, moves inside the syringe to expel the therapeutic agent from the syringe and into the patient's skin.

WO 2004/024211 discloses devices for injecting medications that include an injection needle and a reservoir for containing a supply of the drug painlessly through the needle and into a patient at a substantially constant volumetric flow rate of approximately 0.05 [mu ] l / s approximately 50 [mu] l / s.

WO 2002/02165 discloses a needle device that has a needle retraction mechanism that retracts the needle after removing the device from the surface of the skin (either intentionally or involuntarily). Once the needle is retracted, the device becomes inoperative. The needle can also be made inoperative by flexing it when trying to reuse the device. In another embodiment, a needle opening formed in the base of the housing can be covered to render the needle inoperative when trying to reuse the device. In another embodiment, a needle device has, on the contrary, a needle cap that automatically covers the needle after use.

Patent document WO 2010/029054 discloses a compact and single-use self-administration device for administering medication, which provides means for extending and retracting the hollow needle and an electronic control unit that controls a drive unit, the means of extension and retraction, and interfaces with a start button, a status indicator and a body sensor to automatically administer the medication. WO 2005/037350 discloses a medical device comprising a reservoir adapted to contain a fluid drug therein, and a pump assembly comprising a fluid connector arranged to be operated from an initial state in which the connector of fluid is disposed within the interior of the pump and an actuated state in which fluid communication is established between the interior of the reservoir and the interior of the pump assembly via the fluid connector and the outlet of the fluid connector arranged in the path Flow of the pump assembly.

Object of the invention

The present invention provides:

1. An automatic portable injection device free of a battery to provide a subcutaneous injection of a therapeutic agent into a patient, the automatic portable injection device comprising:

a housing comprising a portion of contact with the patient that can be fixed to the patient; an injection assembly disposed mobilely in the housing containing a hypodermic injection needle for insertion into the patient, the mobile injection assembly between a retracted position in which the injection needle does not protrude outside the housing and a position extended in which the injection needle protrudes out of the housing;

a container provided in the housing to contain the therapeutic agent;

a plunger movably disposed in the container to expel the therapeutic agent from the container in the injection assembly;

a plunger drive mechanism to drive the plunger using a mechanical or hydraulic mechanism inside the vessel;

a retraction activator responsive to a change in the state of the automatic portable injection device from an injection state to a post-injection state, in which the portable automatic injection device enters the post-injection state after administration of a therapeutically effective dose of the therapeutic agent and enters the post-injection state after removal of the portable automatic injection device from the patient before the administration of the therapeutically effective dose of the therapeutic agent; Y

a retraction mechanism to automatically retract the injection assembly from the extended position in the injection state to the retracted position in the post-injection state after activation by the retraction activator.

2. The automatic portable injection device of point [1], in which the container comprises a syringe, the syringe comprising:

a cylinder portion to contain the therapeutic agent; Y

a syringe needle coupled to a distal end of the cylinder portion to establish fluid communication between the cylinder portion of the syringe and the injection needle.

3. The automatic portable injection device of point [2], in which the injection assembly comprises: a partition that is pierceable by the syringe needle of the syringe; Y

a fluid conduit that extends between the injection needle and the septum, in which the perforation of the septum by the syringe needle of the syringe couples the cylinder portion of the syringe and the injection needle; wherein the syringe needle of the syringe is separated from the septum when the device is in a pre-injection state, and in which the syringe needle pierces the septum when the device is in the injection state.

4. The automatic portable injection device of item [1], in which the container comprises a cartridge, the cartridge comprising:

a cylinder portion to contain the therapeutic agent; Y

a septum that is pierceable by a piercing needle.

5. The automatic portable injection device of point [4], wherein the injection assembly comprises: the piercing needle for establishing fluid communication between the cylinder portion of the cartridge and the injection needle; Y

a fluid conduit provided between the injection needle and the piercing needle to establish fluid communication between the injection needle and the cylinder portion of the cartridge;

wherein the septum of the cartridge separates from the piercing needle of the injection assembly when the device is in a pre-injection state, and in which the piercing needle punctures the septum when the device is in the state of injection; Y

wherein the perforation of the partition by the injection needle of the injection assembly establishes fluid communication between the cylinder portion of the cartridge and the injection needle.

6. The automatic portable injection device of the point [1], in which the container is mobile inside the housing between a first position in a pre-injection state and a second position in the injection state, in which the device Portable injection automatic further comprises a container actuator for automatically actuating the container from the first position to the second position, in which a fluid path is established between the injection needle and the container when the injection assembly is in the position extended and the container is in the second position in the injection state. 7. The automatic portable injection device of point [1], in which the plunger drive mechanism expels the therapeutic agent into the patient at a controlled rate in which a volume of the therapeutic agent ranging from 0.8 milliliters to 1 milliliter is administered by the device for a period of time ranging from 5 minutes to 30 minutes.

8. The automatic portable injection device of point [1], in which the piston drive mechanism comprises:

a snail; Y

a belt that couples the deflection mechanism to the snail and the plunger.

9. The automatic portable injection device of point [8], in which the piston drive mechanism further comprises:

a damping mechanism coupled to the snail to regulate the movement of the snail; Y

a gear train that includes one or more gears to couple the snail to the damping mechanism.

10. The automatic portable injection device of point [1], in which the piston drive mechanism comprises:

a diversion mechanism;

one or more ball bearings to couple the plunger deflection mechanism; Y

a damping mechanism coupled to the deflection mechanism and ball bearings to regulate the movement of ball bearings.

11. The automatic portable injection device of point [1], in which the piston drive mechanism further comprises:

a source of a working fluid to provide a hydraulic pressure to expel the therapeutic agent from the container; Y

a fluid conduit provided between the source of the working fluid and the plunger.

12. The automatic portable injection device of point [11], in which the piston drive mechanism further comprises:

a damping mechanism coupled to the container and the source of the working fluid to regulate the expulsion of the therapeutic agent from the container.

13. The automatic portable injection device of point [12], wherein the damping mechanism comprises a flow limiter to maintain the hydraulic pressure downstream of the flow limiter to the vessel at a pressure lower than the hydraulic water pressure above the flow limiter to the source of the working fluid, and in which the flow limiter is coupled to the retraction activator and in which the administration of the therapeutic agent in the container causes the flow limiter to activate the activator of retraction

14. The automatic portable injection device of point [1], further comprising: a needle locking mechanism for automatically locking the injection needle in the retracted position inside the housing in the post-injection state.

15. The automatic portable injection device of the point [14], in which the needle locking mechanism comprises:

a barrier mechanism disposed mobilely over an opening of the injection needle in the housing;

wherein the opening of the injection needle is open and allows the injection needle to protrude out of the housing when the barrier mechanism is in a first position; Y

wherein the opening of the injection needle closes and prevents the injection needle from protruding out of the housing when the barrier mechanism is in a second position.

16. The automatic portable injection device of the point [14], in which the needle locking mechanism comprises:

a mechanism for releasing the needle block sensitive to the retraction of the injection assembly from the extended position in the injection state to the retraction position in the post injection state; Y

a pivoting member coupled to the injection needle and the needle lock release mechanism; wherein the activation of the needle lock release mechanism causes the pivoting member to pivot the injection needle away from an opening of the injection needle in the housing.

17. The automatic portable injection device of the point [1], in which the retraction activator is activated after the administration of a therapeutically effective dose of the therapeutic agent or after the withdrawal of the automatic portable injection device from the patient before terminate the administration of a therapeutically effective dose of the therapeutic agent.

18. The automatic portable injection device of item [1], wherein the therapeutic agent comprises a TNFa inhibitor.

19. The automatic portable injection device of item [1], wherein the therapeutic agent comprises any of a fusion protein, an enzyme, an antibody, or its antigen-binding fragment in a solution.

20. The automatic portable injection device of point [1], in which, after activation by the retraction activator, the retraction mechanism automatically raises an injection button vertically containing the injection needle into the injection assembly .

21. The automatic portable injection device of point [1], in which the retraction activator is coupled to the piston drive mechanism or to a sensor foot provided at the bottom of the housing. Exemplary embodiments provide portable automatic injection devices that can be adhering to a patient's skin or clothing and administering a therapeutic agent within the patient's body by subcutaneous injection at slow controlled injection rates, for example, in a single slow bolus. The exemplary embodiments of the present disclosure provide exemplary portable automatic injection device assembly methods. The exemplary embodiments of the present disclosure also provide methods of using portable automatic injection devices carried by a patient for the slow controlled administration of therapeutic agents. Automatic portable injection devices by way of example reduce or eliminate a burning sensation often felt or perceived by patients using a conventional automatic injection device. The exemplary portable automatic injection devices maintain the sterility of the therapeutic agent container (eg syringe), are easy to use, capable of being preloaded, easy to manufacture and / or do not require aseptic assembly. The portable automatic injection devices provided by the exemplary embodiments may adhere to the patient's skin or clothing to administer any therapeutic agent subcutaneously that includes, but is not limited to, a biological drug, such as, by example, an antibody, insulin, etc.

According to an exemplary embodiment of the present disclosure, an automatic portable injection device is provided to provide a subcutaneous injection of a therapeutic agent in a patient. The device includes a housing comprising a portion of contact with the patient that can be fixed to the patient. The device also includes an injection assembly disposed mobilely in the housing containing a hypodermic injection needle for insertion into the patient, the mobile injection assembly between a retracted position in which the injection needle does not protrude outside the housing and an extended position in which the injection needle protrudes outside the housing. The device also includes a container provided in the housing to contain the therapeutic agent, a plunger movably disposed in the container to expel the therapeutic agent from the container in the injection assembly, and a plunger drive mechanism to drive the plunger inside of the container. The device also includes a retraction activator responsive to a change of state of the portable automatic injection device from an injection state to a post-injection state, and a retraction mechanism to automatically retract the injection assembly from the extended position in the injection state to the retracted position in the post-injection state after activation by the retraction activator.

According to another exemplary embodiment of the present disclosure, a method of subcutaneous injection of a therapeutic agent in a patient is provided. The method includes providing an automatic portable injection device that includes a housing comprising a patient contact portion that can be fixed to the patient. The device also includes an injection assembly disposed mobilely in the housing containing a hypodermic injection needle for insertion into the patient, the mobile injection assembly between a retracted position in which the injection needle does not protrude outside the housing and an extended position in which the injection needle protrudes outside the housing. The device also includes a container provided in the housing to contain the therapeutic agent, a plunger movably disposed in the container to expel the therapeutic agent from the container in the injection assembly, and a plunger drive mechanism to drive the plunger inside of the container. The device also includes a retraction activator responsive to a change of state of the portable automatic injection device from an injection state to a post-injection state, and a retraction mechanism to automatically retract the injection assembly from the extended position in the injection state to the retracted position in the post-injection state after activation by the retraction activator. The method includes attaching the automatic portable injection device to the patient's skin or a garment on the patient using contact with the patient of the housing. The method also includes administering the therapeutic agent on the patient's skin using the automatic portable injection device.

According to another exemplary embodiment of the present disclosure, an automatic portable injection device is provided for subcutaneously injecting a therapeutic agent into a patient. The device includes a housing and a cartridge assembly disposed mobilely within the housing. The cartridge includes a cylinder portion for containing the therapeutic agent, and a hollow needle in fluid communication with the cylinder portion for expelling the therapeutic agent from the cylinder portion. The cartridge also includes a cap to seal the cylinder portion and selectively apply pressure to the therapeutic agent to force the therapeutic agent through the hollow needle. The cartridge further includes a plunger actuator to apply pressure to the cap, and an activating mechanism that drives the plunger actuator to apply pressure to the cap when the cartridge is pressed from a ready position (in a pre-injection state) to a pulsed position. (in an injection state) inside the housing. The activating mechanism drives the plunger actuator so that the therapeutic agent is ejected from the cylinder portion and into the patient at a slow controlled speed with little or no burning sensation felt or perceived by the patient. The device also includes a fixative layer disposed on a contact surface of the patient to secure the device to the patient's skin or clothing or to a patient's garment. The fixative layer may include an adhesive to temporarily fix the automatic portable injection device to the patient at least during the controlled injection of the therapeutic agent.

The automatic portable injection device of the present disclosure includes a retraction mechanism that retract the cartridge from the pressed position to a retracted position (in a post-injection state). The portable automatic injection device also includes a retraction activator that activates the retraction mechanism, the retraction activator is activated when the administration of the therapeutic agent is completed, or is paused due to an elapsed period of time, or when the Automatic portable injection device is removed from the patient, for example, before the administration of the therapeutic agent is completed. The portable automatic injection device operates and operates completely based on mechanical principles or in combination with a controlled reaction to the transition from any state (i.e., a pre-injection state, an injection state, a post-injection state), and controls the injection rate of the therapeutic agent for a period of time that is selected for the comfort, convenience or preference of the patient, or exceeds a period of time for injection by a conventional automatic portable device. In an exemplary embodiment, the period of injection time by an exemplary portable automatic injection device may vary between about ten seconds and about twelve hours. In a preferred embodiment, the period of time may vary between about five minutes and about thirty minutes.

In another exemplary embodiment of the present disclosure, a method of subcutaneous injection of a therapeutic agent in a patient is provided. The method includes providing an automatic portable injection device comprising a housing and a cartridge assembly disposed mobilely within the housing. The cartridge includes a cylinder portion for containing a therapeutic agent, and a hollow needle in fluid communication with the cylinder portion for expelling the therapeutic agent from the cylinder portion. The cartridge also includes a cap to seal the cylinder portion and selectively apply pressure to the therapeutic agent to force the therapeutic agent through the hollow needle. The cartridge further includes a plunger actuator to apply pressure to the cap, and an activating mechanism that drives the plunger actuator to apply pressure to the cap when the cartridge is pressed from a ready position (in a pre-injection state) to a pulsed position. (in an injection state) inside the housing. The activating mechanism drives the plunger actuator so that the therapeutic agent is ejected from the cylinder portion and into the patient at a controlled slow speed and substantially free of any burning sensation.

The method of the present disclosure also includes pressing the cartridge from the ready position to a pressed position within the housing. Pressing the cartridge automatically causes the injection needle used to pierce the patient's skin to project from an opening in the housing to penetrate the patient's skin, and actuates the plunger actuator to apply pressure to the cap so that the agent Therapeutic is administered within the patient at a controlled slow rate and substantially free of any burning sensation.

The method of the present disclosure also includes automatically retracting the cartridge from a pulsed position to a retracted position (in a post-injection state) in the housing when the administration of the therapeutic agent is completed, or is retracted due to an elapsed period of time, or when the automatic portable injection device is removed from the patient's skin or clothing, for example, before the administration of the therapeutic agent is completed.

In an exemplary embodiment of the present disclosure, an automatic portable injection device is provided. The portable automatic injection device provides a subcutaneous injection of a therapeutic agent in a patient. The portable automatic injection device includes a housing that has a patient contact portion that can be fixed to the patient and an inner portion defined by a plurality of walls and that defines at least one open end that opposes the contact portion with the patient The portable automatic injection device also includes a cartridge assembly disposed mobilely within the inner portion of the housing and mobile from any of a ready position, an injection position and a retraction position. The automatic portable injection device further includes an activating mechanism sensitive to a change in the state of the portable automatic injection device from a pre-injection state to an injection state to drive a piston actuator disposed in the cartridge assembly to start the expulsion of a therapeutic agent from the cartridge assembly, and a retraction activator responsive to a change of state of the portable automatic injection device from the injection state to a post-injection state. The portable automatic injection device also includes a retraction mechanism responsive to the retraction activator to automatically retract the patient cartridge assembly when the automatic injection device enters the post-injection state.

In another exemplary embodiment of the present disclosure, a method of subcutaneous injection of a therapeutic agent in a patient is provided. The method includes fixing to a patient an automatic portable injection device comprising a housing having a contact portion with the patient that can be fixed to the patient and an inner portion defined by a plurality of walls and defining at least one open end which opposes the patient contact portion and a cartridge assembly disposed movably within the inner portion of the casing and movable from any of a ready position, an injection position and a retraction position, containing the assembly cartridge the therapeutic agent in a sterile mode that can be preloaded and / or preloaded. The method also includes pressing the cartridge assembly down toward the patient contact portion to cause the portable automatic injection device to enter an injection state from a pre-injection state to automatically project a needle from a needle opening. into the housing and penetrate the patient's skin and expel the therapeutic agent inside the patient to a speed controlled.

Description of the figures

Within the scope of the appended claims, the foregoing and other objects, aspects, features and advantages of the exemplary embodiments will be more apparent and can be better understood with reference to the following description taken in conjunction with the accompanying drawings.

Figure 1A illustrates a first view from one end and a first side view of an exemplary portable device that includes a cartridge assembly in a pre-injection packaged state.

Figure 1B illustrates the first view from one end and the first side view of the exemplary device of Figure 1A before an injection in a pre-injection state in which a needle cover covering the injection needle is removed in preparation for an injection

Figure 1C illustrates the first view from one end and the first side view of the exemplary device of Figure 1A during an injection in an injection state in which the patient's skin is pierced by the injection needle.

Figure ID illustrates the first view from one end and the first side view of the exemplary device of Figure 1A during an injection in an injection state in which a cylinder portion of the device containing a dose of the therapeutic agent is deploys forward inside the device housing. Figure 1E illustrates the first view from one end and the first side view of the exemplary device of Figure A during an injection in an injection state in which a cap of the device is actuated by a plunger actuator to eject the dose of the therapeutic agent of the cylinder portion.

Figure 1F illustrates the first view from one end and the first side view of the exemplary device of Figure 1A after an injection in a post-injection state in which the injection needle retracts into the device housing .

Figure 2A illustrates a first view from one end and a first side view of an exemplary portable device that includes a syringe assembly in a pre-injection packaged state.

Figure 2B illustrates the first view from one end and the first side view of the exemplary device of Figure 2A before an injection in a pre-injection state in which a needle cover covering the injection needle is removed in preparation for an injection

Figure 2C illustrates the first view from one end and the first side view of the exemplary device of Figure 2A during an injection in an injection state in which the patient's skin is pierced by the injection needle.

Figure 2D illustrates the first view from one end and the first side view of the exemplary device of Figure 2A during an injection in an injection state in which a cylinder portion of the device containing a dose of the therapeutic agent is deploys forward inside the device housing. Figure 2E illustrates the first view from one end and the first side view of the exemplary device of Figure 2A during an injection in an injection state in which a cap of the device is actuated by a plunger actuator to eject the dose of the therapeutic agent of the cylinder portion.

Figure 2F illustrates the first view from one end and the first side view of the exemplary device of Figure 2A after an injection in a post-injection state in which the injection needle retracts into the device housing .

Figure 3 is a flow chart of an exemplary method of assembling an automatic portable injection device by way of example.

Figure 4 is a flow chart of an exemplary method of using an exemplary portable automatic injection device.

Figure 5 is a flow chart of an exemplary method of using an exemplary portable automatic injection device for injecting a therapeutic agent into a patient.

Figure 6A illustrates an exemplary portable automatic injection device suitable for linear insertion in a patient in a pre-injection state.

Figure 6B illustrates the exemplary device of Figure 6A in an injection state ready to inject or inject a dose of a therapeutic agent into a patient.

Figure 6C illustrates the exemplary device of Figures 6A and 6B in a post-injection state after the injection of the therapeutic agent into the patient or withdrawn from the patient before the injection of the therapeutic agent is completed.

Figure 7A illustrates an exemplary portable automatic injection device suitable for rotating insertion in a pre-injection state ready for use by a patient.

Figure 7B illustrates the exemplary device of Figure 7A in an injection state ready to inject or inject a dose of a therapeutic agent into a patient.

Figure 7C illustrates the exemplary device of Figures 7A and 7B in a post-injection state after the injection of the therapeutic agent into the patient or withdrawn from the patient before the injection of the therapeutic agent is completed.

Figure 8 is a flow chart of an exemplary assembly method of an automatic portable injection device by way of example.

Figure 9 is a flow chart of an exemplary method of using an exemplary portable automatic injection device.

Figure 10 is a flow chart of an exemplary method of using an exemplary portable automatic injection device for injecting a therapeutic agent into a patient.

Figure 11 illustrates an exemplary cylinder portion in which a distal end of the cylinder portion carries an injection needle that extends substantially along the longitudinal axis of the cylinder portion.

Figure 12 illustrates an exemplary cylinder portion in which a distal end of the cylinder portion carries an injection needle extending approximately 90 degrees with respect to the longitudinal axis of the cylinder portion.

Figure 13 illustrates an exemplary water assembly in which an exemplary adapter couples a syringe needle to an injection needle.

Figure 14 illustrates an exemplary water assembly in which a fluid conduit couples a syringe needle to an injection needle.

Figure 15 illustrates an exemplary transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle.

Figure 16 illustrates an exemplary transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle.

Figure 17 illustrates an exemplary transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle.

Figure 18A illustrates a perspective view of an exemplary portable automatic injection device.

Figure 18B illustrates a disassembled view showing the components of the exemplary device of Figure 18A.

Figure 19A illustrates a side view of an exemplary portable automatic injection device.

Figure 19B illustrates a perspective view showing the components of the device of Figure 19A.

Figure 20A illustrates a perspective view of an exemplary portable automatic injection device.

Figure 20B illustrates a top view of the device of Figure 20A.

Figure 20C illustrates a side view of the transfer mechanism of the device of Figure 20A.

Figure 21A illustrates a perspective view of an exemplary portable automatic injection device that includes an exemplary cartridge assembly.

Figure 21B illustrates a sectional view of the exemplary cartridge assembly of Figure 21A along a longitudinal axis.

Figure 21C illustrates a transparent top view of the exemplary device of Figure 21A. Figure 22 illustrates an exemplary syringe or cartridge actuator that can be used to advance a portion of the cylinder and / or the cartridge assembly from a retract position to an extended position within the housing of an automatic device. portable injection

Figure 23 illustrates an exemplary syringe or cartridge actuator that includes a first portion, a second portion and a hinge portion provided between the first and second portions.

Figure 24 illustrates a schematic of a portion of an exemplary automatic injection device that includes a plunger drive mechanism employing a snail and a viscous damping mechanism.

Figure 25 illustrates an automatic portable injection device may include a platform, a slide car coupled to the platform, and a cartridge assembly mounted on the slide car.

Figure 26 illustrates that an automatic portable injection device may include a platform, a slide car coupled to the platform and a cartridge assembly mounted on the slide car.

Figure 27 is a top view through a cover of an exemplary automatic injection device that includes a plunger drive mechanism for automatically actuating a plug in a cylinder portion.

Figure 28 is a side view of the exemplary automatic injection device of Figure 27 showing a snail and a damping mechanism.

Figure 29 is a perspective view through a cover of the exemplary automatic injection device of Figure 27.

Figure 30 illustrates the x and y coordinates (in inches) of cam profiles for: (i) the combination of spring 1 and a viscous damper, (ii) the combination of spring 1 and an exhaust, (iii) the combination of spring 2 and a viscous damper, and (iv) the combination of spring 2 and an exhaust.

Figure 31 illustrates a graph of therapeutic agent flow rates (in milliliters per minute) versus time (in seconds) administered by: (i) the combination of spring 1 and a viscous buffer, (ii) the combination of spring 1, a viscous damper and a cam coil, (iii) the combination of spring 1 and an exhaust, (iv) the combination of spring 1, an exhaust and a cam coil, (v) the combination of spring 2 and a viscous damper, (vi) the combination of spring 2, a viscous damper and a cam coil, (vii) the combination of spring 2 and an exhaust, (viii) the combination of spring 2, an exhaust and a cam coil, and (ix ) and an ideal flow rate in which the therapeutic agent is administered at a substantially constant rate.

Figure 32 illustrates a graph of the therapeutic agent volume (in milliliters) versus time (in seconds) administered by the combinations of components of Figure 31.

Figure 33 illustrates a graph of the volume of therapeutic agent (in milliliters) versus time (in seconds) administered using: (i) a damping mechanism G having a damping coefficient of approximately 10.3 lbf * s / in ( 18,025 N s / cm) with a gear ratio of 4: 1, (ii) a damping mechanism B that has a damping coefficient of approximately 15.1 lbf * s / in (26,440 Ns / cm) with a ratio of 4: 1 gears, (iii) a damping mechanism K having a damping coefficient of approximately 18.9 lbf * s / in (33.093 Ns / cm) with a gear ratio of 4: 1, (iv) a damping mechanism V having a damping coefficient of approximately 24.9 lbf * s / in (43.599 Ns / cm) with a gear ratio of 4: 1, (v) a damping mechanism G having a damping coefficient of approximately 25.1 lbf * s / in (43,950 Ns / cm) with a gear ratio of 6.25: 1, (vi) a mecanism or damping B having a damping coefficient of approximately 37.0 lbf * s / in (64,787 Ns / cm) with a gear ratio of 6.25: 1, (vii) a damping mechanism K having a coefficient of damping of approximately 46.2 lbf * s / in (80,896 Ns / cm) with a gear ratio of 6.25: 1, (viii) a damping mechanism V having a damping coefficient of approximately 60.7 lbf * s / in (106,285 Ns / cm) with a gear ratio of 6.25: 1, (ix) a damping mechanism G having a damping coefficient of approximately 164 lbf * s / in (287.16 Ns / cm) with a gear ratio of 16: 1, (x) a damping mechanism B that has a coefficient of damping of approximately 242 lbf * s / in (423.74 N s / cm) with a gear ratio of 16: 1, (xi) a damping mechanism K having a damping coefficient of approximately 303 lbf * s / in (530.55 Ns / cm) with a gear ratio of 16: 1, (xii) a damping mechanism V that has a damping coefficient of approximately 398 lbf * s / in (696.89 Ns / cm) with a gear ratio of 16: 1, and (xiii) an ideal flow rate in which the therapeutic agent is administered at a substantially constant rate.

Figure 34 illustrates a graph of example torque pairs of the shock absorber (which can be extrapolated from the displacement of the piston actuator) versus the damper speeds (in rpm) for model G, B, K shock absorbers and V that have increasing damping coefficients.

Figure 35 illustrates a graph of the volume of therapeutic agent (in milliliters) versus time (in seconds) administered by different syringes by way of example using a model V buffer that has a damping coefficient of approximately 24.9 lbf * s / in (43.599 Ns / cm) and an example gear ratio of 4: 1.

Figure 36 illustrates a graph of the volume of therapeutic agent (in milliliters) administered and the diameter of the snail or cam coil (in inches) versus time (in seconds).

Figure 37 illustrates a graph of the volume of therapeutic agent (in milliliters) administered versus time (in seconds) achieved by: (i) a first buffer at room temperature, (ii) the first buffer at approximately 40 degrees Fahrenheit (in a refrigerator), (iii) a second shock absorber, (iv) the second shock absorber at approximately 0 degree Fahrenheit (in a freezer), (v) a third shock absorber that has manufacturing variability with respect to the first and second shock absorbers, and (vi) a fourth shock absorber that has manufacturing variability with respect to the first and second shock absorbers.

Figure 38 illustrates a schematic of a portion of an exemplary automatic injection device that includes a plunger drive mechanism employing a snail and an exhaust mechanism. Figure 39 illustrates an exemplary plunger drive mechanism that employs one or more linear thrust mechanisms to provide a force to express a therapeutic agent of the cylinder portion of an automatic portable injection device.

Figure 40 illustrates an exemplary plunger drive mechanism that employs one or more clock springs to provide a force for expressing a therapeutic agent of the cylinder portion of an automatic portable injection device.

Figure 41 is a schematic of an exemplary automatic injection device that includes a plunger drive mechanism that employs one or more fluid circuits.

Figure 42 is an exemplary automatic injection device that employs one or more fluid circuits to see in perspective a force to a plug to express a dose of a therapeutic agent from a cylinder portion.

Figure 43 illustrates a graph of the cumulative amount of therapeutic agent (in grams) versus time (in seconds) as administered by an exemplary administration system at an exemplary administration pressure of approximately 16.5 psi (1.15 kg / cm2).

Figure 44 illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) versus time (in seconds) as administered by an exemplary administration system that includes a first flow limiter.

Figure 45 illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) versus time (in seconds) as administered by an exemplary administration system that includes a second flow limiter.

Figure 46 is a schematic drawing of an exemplary automatic injection device that employs one or more fluid circuits to provide a force to express a therapeutic agent of a cartridge assembly.

Figure 47 is a top view of the exemplary device of Figure 46.

Figure 48 illustrates a top view of an exemplary automatic injection device showing a conduit that couples the master cylinder to a flow limiter, a conduit that couples the flow limiter to the plug, and a conduit that couples the master cylinder to a retraction mechanism by means of a valve. Figure 49 illustrates a schematic diagram of the device of Figure 48.

Figure 50 illustrates a graph of the pressure after a control valve and behind a plug (in psi) versus time (in seconds) in an exemplary embodiment.

Figure 51 illustrates a side view of an exemplary automatic injection device in which the housing of the portable automatic injection device includes a skin sensing foot.

Figures 52A and 52B illustrate an exemplary needle protection system that maintains an injection needle in a retracted position within a housing of an exemplary automatic injection system.

Figures 53A and 53B illustrate another exemplary needle protection system provided in an exemplary automatic injection system.

Figure 54 illustrates another exemplary needle protection system provided in an exemplary automatic injection system.

Figure 55 illustrates another exemplary needle protection system provided in an exemplary automatic injection system.

Detailed description of the invention

Subcutaneous injection is a primary mode of administration of therapeutic agent and involves administering a bolus of a therapeutic agent to a patient. Subcutaneous injections are highly effective in administering various therapeutic agents that include insulin, vaccines and drugs, such as morphine. Automatic injection devices offer an alternative to a syringe for administering a therapeutic agent and allow patients to self-administer subcutaneous injections of therapeutic agents. Conventional automatic injection devices include portable automatic injection devices and patch pumps, which are patient-mounted self-adhesive autoinjectors. In use, a patch pump containing a therapeutic agent is mounted on a patient's skin or clothing and is activated to inject the therapeutic agent into the patient's. Conventional patch pumps are normally charged by a patient before use. In addition, certain conventional patch pumps have an exposed needle inside the pump, and thus require a sterile secondary container to maintain sterility.

Studies have shown that there is a direct correlation between the injection speed of certain therapeutic agents and the pain perceived by a patient after the injection of the therapeutic agents or agents. Some therapeutic agents cause pain, for example, a burning or stinging sensation when injected quickly into the patient's. The sensation of pain may be the result of a physiological response of the patient's skin to the subcutaneous injection of a therapeutic agent. Large volumes of any therapeutic agent, greater than one milliliter, can also cause pain when injected into the skin. Antibodies, and portions thereof, are exemplary therapeutic agents that are less painful when administered at slow injection rates. Currently, there are no commercially viable conventional patch pumps that effectively deal with the discomfort associated with the rapid injection speeds of portable automatic injection devices.

Exemplary embodiments of the present disclosure are described below with reference to certain illustrative embodiments. Although the exemplary embodiments of the present disclosure are described with respect to the use of an automatic portable injection device to provide an injection of a dose of a medication liquid, a person skilled in the art will recognize that the exemplary embodiments They are not limited to illustrative embodiments and that automatic injection devices by way of example can be used to inject any suitable substance into a patient. In addition, the components of exemplary automatic injection devices and the methods of manufacturing and use of the exemplary automatic injection devices of the present disclosure are not limited to the illustrative embodiments described below.

An exemplary automatic injection device syringe assembly of the present disclosure may contain a dose of a TNFa inhibitor. In an exemplary embodiment of the present disclosure, the TNFa inhibitor can be a human TNFa antibody or its antigen binding portion. In an exemplary embodiment of the present disclosure, the human TNFa antibody or its antigen binding portion may be adalimumab or golimumab.

The exemplary embodiments of the present disclosure provide portable automatic injection devices that can adhere to the patient's skin or clothing and administer a therapeutic agent to the patient by subcutaneous injection at slow controlled injection rates, for example, in A single slow bolus. The slow controlled injection rates achieved by the devices by way of example minimize the sensation of pain associated with a volume of a therapeutic agent entering the patient's tissue. Exemplary time durations for slow administration achieved by example devices may vary. from about 5 minutes to about 30 minutes, but are not limited to this interval by way of example. The exemplary volumes of the therapeutic agent that can be administered by the example devices may vary from about 0.8 milliliters to about 1 milliliter, but are not limited to this range by way of example. In addition, the exemplary devices of the present disclosure can advantageously minimize inflections in the administration profile over time of the therapeutic agent.

The exemplary embodiments of the present disclosure minimize the size wrap of automatic injection devices by way of example, and provide scalable solutions with configurable administration times and administration profiles that can be used for a range of agent viscosities therapeutic.

The exemplary embodiments of the present disclosure provide portable automatic injection devices that administer a therapeutic agent in a patient by subcutaneous injection at slow controlled injection rates, for example, in a single slow bolus without battery or other component feeding. require electric current or charge to operate. The exemplary embodiments of the present disclosure also provide methods of using portable automatic injection devices for the slow controlled administration of therapeutic agents. The portable automatic injection devices provided by the exemplary embodiments of the present disclosure may be preloaded prior to administration to the patient, maintain the sterility of the therapeutic agent and all subcutaneous contact surfaces (i.e., a hypodermic needle and one or more partitions) to avoid the need for aseptic assembly and treat the discomfort perceived by the patient due to injection by conventional portable automatic injection devices. The exemplary portable automatic injection devices of the present disclosure include a portion of primary therapeutic cylinder that maintains sterility and, therefore, does not require aseptic assembly. The exemplary portable automatic injection devices of the present disclosure are disposable, easy to use, capable of being preloaded and can substantially or completely eliminate the burning sensation frequently experienced by a patient using an automatic portable injection device. The portable automatic injection devices provided by the exemplary embodiments of the present disclosure may be used to administer any therapeutic agent that can be administered subcutaneously that includes, but is not limited to, an antibody or insulin, etc.

I. Definitions

Certain terms are defined in this section to facilitate the understanding of the exemplary embodiments.

The automatic portable injection device of the exemplary embodiments of the present disclosure may include a "therapeutically effective amount" or a "prophylactically effective amount" of an antibody or antibody portion of the present disclosure. A "therapeutically effective amount" refers to an amount effective, at doses and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the antibody, antibody portion, or other TNFa inhibitor may vary according to factors such as the disease status, age, sex and weight of the patient, and the ability of the antibody, antibody portion, or other inhibitor. of TNFa to elicit a desired response in the patient. A therapeutically effective amount is also one in which any toxic or harmful effect of the antibody, antibody portion, or other TNFa inhibitor, is compensated for the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at doses and for periods of time necessary, to achieve the desired prophylactic result. Normally, since a prophylactic dose is used in patients before or at an earlier stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount.

The terms "substance" and "therapeutic agent" refer to any type of drug, biologically active agent, biological substance, chemical substance or biochemical substance that is capable of being administered in a therapeutically effective amount to a patient using automatic injection devices. as an example. Exemplary substances include, but are not limited to, agents in a liquid state. Such agents may include, but are not limited to, adalimumab (HUMIRA®) and proteins that are in a liquid solution, for example, fusion proteins and enzymes. Examples of proteins in solution include, but are not limited to, Pulmozyme (dornase alfa), Regranex (becaplermin), Activase (alteplase), Aldurazyme (laronidase), Amevive (alefacept), Aranesp (darbepoetin alfa), becaplermin concentrate, Betaseron (beta-lb interferon), BOTOX (botulinum toxin type A), Elitek (rasburicase), Elspar (asparaginase), Epogen (epoetin alfa), Enbrel (etanercept), Fabrazyme (beta agalsidase), Infergen (interferon alfacon-1) , Intron A (interferon alfa-2a), Kineret (anakinra), MYOBLOC (botulinum toxin type B), Neulasta (pegfilgrastim), Neumega (oprelvekin), Neupogen (filgrastim), Ontak (denileukin diftitox), PEGASYS (peginterferon alfa-2 ), Proleukin (aldesleukin), Pulmozyme (dornase alfa), Rebif (interferon beta-la), Regranex (becaplermina), Retavase (reteplasa), Roferon-A (interferon alfa-2), TNKase (Tenecteplase) and Xigris (drotrecogin alfa ), Arcalyst (rilonacept), Nplate (romiplostim), Mircera (methoxypolyethylene glycol betaine), Cin ryze (C1 esterase inhibitor), Elaprase (idursulfase), Myozyme (alpha alglucosidase), Orencia (abatacept), Naglazyme (galsulfase), Kepivance (palifermin) and Actimmune (gamma-lb interferon).

A protein in solution can also be an immunoglobulin or its antigen binding fragment, such as an antibody or its antigen binding portion. Examples of antibodies that can be used in an exemplary automatic injection device include, but are not limited to, chimeric antibodies, non-human antibodies, human antibodies, humanized antibodies and domain antibodies (dAbs). In an exemplary embodiment, the immunoglobulin or its antigen-binding fragment is an anti-TNFa antibody and / or an anti-IL-12 (for example, it can be a dual domain variable immunoglobulin (DVD) IgTM). Other examples of immunoglobulins or their antigen binding fragments that can be used in the methods and compositions of the exemplary embodiments include, but are not limited to, 1D4.7 (anti-IL-12 / IL-23 antibody; Abbott Laboratories); 2.5 (E) mg1 (anti-IL-18; Abbott Laboratories); 13C5.5 (anti-IL-13 antibody; Abbott Laboratories); J695 (anti-IL-12; Abbott Laboratories); Afelimomab (Fab 2 anti-TNF; Abbott Laboratories); HUMIRA (adalimumab) Abbott Laboratories); Campath (alemtuzumab); CEA-Scan Arcitumomab (fragment fab); Erbitux (cetuximab); Herceptin (trastuzumab); Myoscint (imciromab pentetate); ProstaScint (penromide of capromab); Remicade (infliximab); ReoPro (abciximab); Rituxan (rituximab); Simulect (basiliximab); Synagis (palivizumab); Verluma (nofetumomab); Xolair (omalizumab); Zenapax (daclizumab); Zevalin (ibritumomab tiuxetan); Orthoclone OKT3 (muromonab-CD3); Panorex (edrecolomab); Mylotarg (gemtuzumab ozogamycin); golimumab (centocor); Cimzia (certolizumab pegol); Soliris (eculizumab); CNTO 1275 (ustekinumab); Vectibix (panitumumab); Bexxar (tositumomab and I131 tositumomab); and Avastin (bevacizumab).

Additional examples of immunoglobulins, or their antigen binding fragments, that can be used in the methods and compositions of the exemplary embodiments include, but are not limited to, proteins comprising one or more of the following: the variable region of the light chain of D2E7 (SEQ ID NO: 1), the variable region of the heavy chain of D2E7 (SEQ ID NO: 2), the CDR3 of the variable region of the light chain of D2E7 (SEQ ID NO: 3) , the CDR3 of the heavy chain variable region of D2E7 (SEQ ID NO: 4), the CDR2 of the light chain variable region of D2E7 (SEQ ID NO: 5), the CDR2 of the variable region of the chain D2E7 (SEQ ID NO: 6), the CDR1 of the light chain variable region of D2E7 (SEQ ID NO: 7), the ^c D ^r 1 of the heavy chain variable region of D2E7 (SEQ ID NO : 8), the variable region of the light chain of 2SD4 (SEQ ID NO: 9), the variable region of the heavy chain of 2SD4 (SEQ ID NO: 10), the CDR3 of the light chain goes Reliable 2SD4 (SEQ ID NO: 11), the CDR3 of the EPB12 variable light chain (SEQ ID NO: 12), the CDR3 of the VL10E4 variable light chain (SEQ ID NO: 13), the CDR3 of the chain VL100A9 variable light (SEQ ID NO: 14), the CDR3 of the VLL100D2 variable light chain (SEQ ID NO: 15), the CDR3 of the VLL0F4 variable light chain (SEQ ID NO: 16), the CDR3 of the LOE5 variable light chain (SEQ ID NO: 17), the CDR3 of the VLLOG7 variable light chain (SEQ ID NO: 18), the CDR3 of the VLLOG9 variable light chain (SEQ ID NO: 19), the CDR3 of the variable light chain of VLLOH1 (SEQ ID NO: 20), the CDR3 of the variable light chain of VLLOH10 (SEQ ID NO: 21), the CDR3 of the variable light chain of VL1B7 (SEQ ID NO: 22), the CDR3 of the variable light chain of VL1C1 (SEQ ID NO: 23), the CDR3 of the variable light chain of VL0.1F4 (SEQ ID NO: 24), the CDR3 of the variable light chain of VL0.1H8 (SEQ ID NO: 25), the CDR3 of the LOE7.A variable light chain (SEQ ID NO: 26), the CDR of the heavy chain variable region of 2SD4 (SEQ ID NO: 27), the CDR of the heavy chain variable region of VHIBI 1 (SEQ ID NO: 28), the CDR of the heavy chain variable region of VH1D8 (SEQ ID NO: 29), the CDR of the heavy chain variable region of VH1A11 (SEQ ID NO: 30), the CDR of the heavy chain variable region of VH1B12 (SEQ ID No: 31), the CDR of the heavy chain variable region of VH1E4 (SEQ ID NO: 32), the CDR of the heavy chain variable region of VH1F6 (SEQ ID NO: 33), the CDR of the heavy chain variable region of 3C-H2 (SEQ ID NO: 34) and the CDR of the heavy chain variable region of VH1-D2.N (SEQ ID NO: 35).

The term "human TNFa" (abbreviated herein hTNFa, or simply hTNF) refers to a human cytokine that exists as a secreted form of 17 kD and a membrane associated form of 26 kD, whose biologically active form is composed by a trimer of 17 kD molecules not covalently bound. The structure of hTNFa is further described in, for example, Pennica, D., et al. (1984) Nature 312: 724-729; Davis, J.M., et al. (1987) Biochem, 26: 1322-1326; and Jones, E.Y., et al. (1989) Nature 338: 225-228. The term human TNFa is intended to include recombinant human TNFa (rhTNFa), which can be prepared by conventional recombinant expression methods or commercially purchased (R&D Systems, Catalog No. 210-TA, Minneapolis, MN). TNFa is also called TNF.

The term "TNFa inhibitor" refers to an agent that interferes with the activity of TNFa. The term also includes each of the human anti-TNFa antibodies (used interchangeably herein with TNFa antibodies) and portions of antibody described herein, as well as those described in U.S. Pat. Nos. 6,090 .382; 6,258,562; 6,509,015; 7,223,394; and 6,509,015. In one embodiment, the TNFa inhibitor used in the present disclosure is an anti-TNFa antibody, or its fragment, which includes infliximab (Remicade®, Johnson and Johnson; described in U.S. Patent No. 5,656,272) ; CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody); CDP 870 (a fragment of humanized monoclonal anti-TNF-alpha antibody); an anti-TNF dAb (Peptech); CNTO 148 (golimumab; Centocor, see patent documents WO 02/12502 and US 7,521,206 and US 7,250,165); and adalimumab (HUMIRA® Abbott Laboratories, a human anti-TNF mAb, described in US 6,090,382 as D2E7). Additional TNF antibodies that can be used in the present disclosure are described in US Pat. No. 6,593,458; 6,498,237; 6,451,983; and 6,448,380. In another embodiment, the TNFa inhibitor is a TNF fusion protein, for example, etanercept (Enbrel®, Amgen; described in WO 91/03553 and WO 09/406476). In another embodiment, the TNFa inhibitor is a recombinant TNF binding protein (r-TBP-I) (Serono).

In one embodiment, the term "TNFa inhibitor" excludes infliximab. In one embodiment, the term "TNFa inhibitor" excludes adalimumab. In another embodiment, the term "TNFa inhibitor" excludes adalimumab and infliximab.

In one embodiment, the term "TNFa inhibitor" excludes etanercept, and, optionally, adalimumab, infliximab and adalimumab and infliximab.

In one embodiment, the term "TNFa antibody" excludes infliximab. In one embodiment, the term "TNFa antibody" excludes adalimumab. In another embodiment, the term "TNFa antibody" excludes adalimumab and infliximab.

The term "antibody" refers to immunoglobulin molecules generally composed of four polypeptide chains, two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. Each heavy chain comprises a variable region of the heavy chain (abbreviated herein HCVR or VH) and a constant region of the heavy chain. The constant region of the heavy chain comprises three domains, CH1, CH2 and CH3. Each light chain comprises a variable region of the light chain (abbreviated herein LCVR or VL) and a constant region of the light chain. The constant region of the light chain comprises a domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDR), interspersed with regions that are more conserved, called structural regions (FR). Each VH and VL is composed of three CDR and four FR, arranged from the amino end to the carboxy end in the following order: FR1, CDRl, FR2, CDR2, FR3, CDR3, FR4. The antibodies of the present disclosure are described in more detail in US Pat. No. 6,090,382; 6,258,562; and 6,509,015.

The term "antigen binding portion" of an antibody (or simply "antibody portion") refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (eg, hTNFa). Fragments of a full length antibody can perform the antigen binding function of an antibody. Examples of binding fragments encompassed within the term "antigen binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) an F (ab ') 2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al. (1989) Nature 341: 544-546), which consists of a VH domain or VL; (vi) an isolated complementarity determining region (CDR); and (vii) a dual variable domain immunoglobulin (DVD-Ig). In addition, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be linked, using recombinant methods, by a synthetic linker that allows them to be prepared as a single chain protein in which the VL regions and VH pair to form monovalent molecules (known as single chain Fv (scFv); see, for example, Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883). Such single chain antibodies are also encompassed within the term "antigen binding portion" of an antibody. Other forms of single chain antibodies, such as diabodies, are also encompassed. Diabodies are bivalent bispecific antibodies in which the VH and VL domains are expressed in a single polypeptide chain, but using a linker that is too short to allow pairing between the two domains in the same chain, thus forcing the domains pair with complementary domains of another chain and create two antigen binding sites (see, for example, Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448; Poljak et al. (1994 ) Structure 2: 1121-1123). The antibody portions of the present disclosure are described in more detail in US Pat. No. 6,090,382; 6,258,562; and 6,509,015.

The term "recombinant human antibody" refers to all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a combinatorial library of recombinant human antibodies (described further below), antibodies isolated from an animal (eg, a mouse) that is transgenic for human immunoglobulin genes (see, for example, Taylor et al. (1992 ) Nucl. Acids Res. 20: 6287) or antibodies prepared, expressed, created or isolated by any other means involving the splicing of human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from the human germline immunoglobulin sequences. In certain embodiments, however, said recombinant human antibodies are subjected to in vitro mutagenesis (or, when a transgenic animal is used for human Ig sequences, in vivo somatic mutagenesis ) and thus the amino acid sequences of the VH and VL regions of Recombinant antibodies are sequences that, although derived from and related to VH and VL sequences of the human germline, may not exist naturally within the repertoire of human germline antibodies in vivo.

Such chimeric, humanized, human and dual specific antibodies can be produced by recombinant DNA techniques known in the art, for example, using the methods described in PCT International Application No. PCT / US86 / 02269; European Patent Application No. 184,187; European Patent Application No. 171,496; European Patent Application No. 173,494; PCT International Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Application No. 125,023; Better et al. (1988) Science 240: 1041-1043; Liu et al. (1987) Proc. Natl Acad. Sci. USA 84: 3439-3443; Liu et al. (1987) J. Immunol. 139: 3521-3526; Sun et al. (1987) Proc. Natl Acad. Sci. USA 84: 214-218; Nishimura et al. (1987) Cancer Res. 47: 999-1005; Wood et al. (1985) Nature 314: 446-449; Shaw et al. (1988) J. Natl. Cancer Inst. 80: 1553-1559; Morrison (1985) Science 229: 1202-1207; Oi et al. (1986) BioTechniques 4: 214; U.S. Patent No. 5,225,539; Jones et al. (1986) Nature 321: 552-525; Verhoeyan et al. (1988) Science 239: 1534; and Beidler et al. (1988) J. Immunol. 141: 4053-4060, Queen et al. (1989) Proc. Natl Acad. Sci. USA 86: 10029-10033 (1989); U.S. Patent No. 5,530,101; U.S. Patent No. 5,585,089; US 5,693,761; US 5,693,762; WO 90/07861; and US 5,225,539.

The term "isolated antibody" refers to an antibody that is substantially free of other antibodies that have different antigenic specificities (for example, an isolated antibody that specifically binds hTNFa and is substantially free of antibodies that specifically bind antigens other than hTNFa). An isolated antibody that specifically binds to hTNFa may have cross reactivity with other antigens, such as TNFa molecules from other species. In addition, an isolated antibody may be substantially free of other cellular material and / or chemicals.

The term "neutralizing antibody" (or an "antibody that neutralized the activity of hTNFa") refers to an antibody whose binding to hTNFa results in the inhibition of the biological activity of hTNFa. This inhibition of the biological activity of hTNFa can be evaluated by measuring one or more indicators of the biological activity of hTNFa, such as the cytotoxicity induced by hTNFa (either in vitro or in vivo), cellular activation induced by hTNFa and the binding of hTNFa to hTNFa receptors. These indicators of the biological activity of hTNFa can be evaluated by one or more of several conventional in vitro or in vivo assays known in the art (see US Patent No. 6,090,382). Preferably, the ability of an antibody to neutralize hTNFa activity is evaluated by inhibition of hTNFa-induced cytotoxicity of L929 cells. As an additional or alternative parameter of hTNFa activity, the ability of an antibody to inhibit hTNFa-induced expression of ELAM-1 in HUVEC can be evaluated as a measure of hTNFa-induced cellular activation.

The term "surface plasmon resonance" refers to an optical phenomenon that allows the analysis of biospecific interactions in real time by detecting alterations in protein concentrations within a biosensor matrix, for example, using the BIAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ). For additional descriptions, see Example 1 of US Pat. 6,258,562 and Jonsson et al. (1993) Ann. Biol. Clin. 51:19; Jonsson et al. (1991) Biotechniques 11: 620-627; Johnsson et al. (1995) J. Mol. Recognit 8: 125; and Johnnson et al. (1991) Anal. Biochem, 198: 268.

The term "Kdis' refers to the dissociation rate constant for the dissociation of an antibody from the antibody / antigen complex.

The term "Kd" refers to the dissociation constant of a particular antibody-antigen interaction.

The term "IC50" refers to the concentration of the inhibitor required to inhibit the biological endpoint of interest, for example, neutralizing cytotoxicity activity.

The term "dose" or "dosage" refers to an amount of a substance, such as a TNFa inhibitor, which is preferably administered to a patient using the automatic portable injection device of the invention. In one embodiment, the dose comprises an effective amount, for example, which includes, but is not limited to, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg and 160 mg of the TNFa inhibitor adalimumab.

The term "dosage" refers to the administration of a substance (for example, an anti-TNFa antibody) to achieve a therapeutic objective (for example, treatment of rheumatoid arthritis).

The term "dosage schedule" describes a treatment program for a substance, such as a TNFa inhibitor, for example, a treatment program for a prolonged period of time and / or throughout the course of treatment, for example, administering a first dose of a TNFa inhibitor at week 0, followed by a second dose of a TNFa inhibitor in a biweekly dosing schedule.

The term "biweekly dosage schedule", "biweekly dosage" and "biweekly administration" refer to the temporal evolution of administering a substance (eg, an anti-TNFa antibody) to a patient to achieve a therapeutic goal, for example, during the entire course of treatment The biweekly dosage schedule is not intended to include a weekly dosage schedule. Preferably, the substance is administered every 9 to 19 days, more preferably every 11 to 17 days, even more preferably every 13 to 15 days, and most preferably every 14 days. In one embodiment of the present disclosure, the biweekly dosage schedule is initiated in a patient at week 0 of treatment. In another embodiment of the present disclosure, a maintenance dose is administered in a biweekly dosage schedule. In one embodiment of the present disclosure, both loading and maintenance doses are administered according to a biweekly dosage schedule. In an embodiment of the present disclosure, the biweekly dosage includes a dosage schedule in which the doses of a TNFa inhibitor are administered to a patient every two weeks starting at week 0. In one embodiment of the present disclosure, the biweekly dosage includes a dosage schedule where the Doses of a TNFa inhibitor are administered to a patient every two weeks consecutively for a given period of time, for example, 4 weeks, 8 weeks, 16, weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks, etc. Biweekly dosing methods are also described in US 2003/0235585.

The term "combination", as in the expression "a first agent in combination with a second agent", includes the co-administration of a first agent and a second agent, which for example can be dissolved or mixed in the same pharmaceutically acceptable carrier , or the administration of a first agent, followed by the second agent, or the administration of the second agent, followed by the first agent.

The term "concomitant", as in the term "concomitant therapeutic treatment", includes administering an agent in the presence of a second agent. A concomitant therapeutic treatment method includes methods in which the first, second, third substance, or additional substances are co-administered. A concomitant therapeutic treatment method also includes methods in which the first additional agent or agents are administered in the presence of a second additional substance or substances, in which the second additional agent or agents, for example, may have been previously administered. A concomitant therapeutic treatment method can be performed stepwise by different patients. For example, a subject may administer a first agent to a patient and a second subject may administer a second substance to the patient, and the administration stages may be executed at the same time, or at almost the same time, or at distant times, while The first substance (and additional substances) is after administration in the presence of the second substance (and additional substances). The actor and the patient can be the same entity (for example, human).

The term "combination therapy" refers to the administration of two or more therapeutic substances, for example, an anti-TNFa antibody and another drug. The other drug (s) can be administered concomitantly with, before or after the administration of an anti-TNFa antibody.

The term "treatment" refers to therapeutic treatment, as well as prophylactic or suppressive measures, for the treatment of a disorder, such as a disorder in which TNFa is harmful, for example, rheumatoid arthritis. The term "patient" or "user" refers to any type of animal, human or non-human, that can be injected with a substance using automatic injection devices by way of example.

The terms "automatic portable injection device" and "portable auto-injector" refer to a device carried by a patient that allows the patient to self-administer a therapeutically effective dose of a therapeutic agent, either by attaching the portable device directly to their skin or fixing the portable device to a garment that allows the penetration of a hypodermic needle, in which the portable device differs from a conventional syringe by the inclusion of a mechanism to automatically administer the therapeutic agent to the patient by injection when the mechanism.

The terms "syringe" and "cartridge" encompass a portion of a sterile cylinder that is filled with a dose of a therapeutic agent before distribution or sale to a patient or other non-medical professional for administration of the therapeutic agent to a patient. In an exemplary embodiment of the present disclosure, a distal end of the cylinder portion of a syringe can be coupled to a sterile hypodermic needle. In an exemplary embodiment of the present disclosure, a distal end of the cylinder portion of a cartridge may not engage a needle. That is, in exemplary embodiments of the present disclosure, a syringe can be a cartridge with a hollow needle previously attached coupled to its cylinder portion.

The exemplary embodiments of the present disclosure described herein with reference to a syringe assembly can also be implemented using a cartridge assembly. Similarly, the exemplary embodiments of the present disclosure described herein with reference to a cartridge assembly can also be implemented using a syringe assembly.

The term "container" refers to both a syringe and a cartridge that can be used in an exemplary portable automatic injection device to contain a dose of a therapeutic agent.

The term "injection needle" refers to a needle in an automatic portable injection device that is inserted into a patient's body to deliver a dose of a therapeutic agent into the patient's body. In an exemplary embodiment of the present disclosure, the injection needle can be directly coupled to or in contact with a syringe or cartridge assembly containing the dose of the therapeutic agent. In another exemplary embodiment of the present disclosure, the injection needle can be indirectly coupled to the syringe or cartridge assembly, for example, by a syringe needle and / or a transfer mechanism that provides fluid communication between the syringe. or cartridge and injection needle.

The term "syringe needle" refers to a needle in an automatic portable injection device that is coupled to or in contact with a syringe or cartridge assembly to transport a dose of a therapeutic agent from the syringe or cartridge assembly to a injection needle that, in turn, administers the therapeutic agent in a patient's body. In an exemplary embodiment, the syringe needle is not inserted into the patient's body. In another exemplary embodiment, the syringe needle can be inserted into the patient's body. In an exemplary portable automatic injection device of the present disclosure that includes a syringe assembly, the syringe needle can be directly coupled to the cylinder portion of the syringe and can be in fluid communication with the cylinder portion. In an exemplary portable automatic injection device of the present disclosure that includes a cartridge assembly, the syringe needle may be provided separately from the cylinder portion of the cartridge, for example, within an injection button or a transfer mechanism During an injection stage, the syringe needle can be inserted at a distal end of the cylinder portion of the cartridge to establish fluid communication between the syringe needle and the cylinder portion.

The term "pre-injection state" refers to a state of an automatic portable injection device before the start of the administration of a therapeutic agent contained in the device.

The term "injection state" refers to one or more states of an automatic portable injection device during the administration of a therapeutic agent contained in the device.

The term "post-injection state" refers to the end of the administration of a therapeutically effective dose of a therapeutic agent contained in the device and the withdrawal of the patient device before the end of the administration of a therapeutically effective dose of the therapeutic agent.

The term "slow" refers to a rate of administration of a volume of a therapeutic agent. In an exemplary embodiment of the present disclosure, a volume of about 0.1 milliliters to about 1 milliliter or more can be administered in a period of administration time of about ten seconds to about twelve hours. In a preferred embodiment, the period of administration time may vary from about five minutes to about thirty minutes.

The term "clothing" refers to any suitable layer on the body of a patient to which an automatic portable injection device can be attached or attached by way of example. The garment can thus form an intermediate layer between the device and the patient's skin and can be used to indirectly couple the device to the patient's skin. In an exemplary embodiment of the present disclosure, the garment can be clothing fitted on the patient's body, for example, nylon stockings. In another exemplary embodiment of the present disclosure, the garment can be a layer on the patient's skin that includes, but is not limited to, a medical tape, a bandage, and the like. In another exemplary embodiment of the present disclosure, the garment can be a coupling mechanism that adheres the device in the vicinity of the patient's skin that includes, but is not limited to, a sleeve that can be adjusted around of a portion of the patient's body, a belt, a bandage (for example, a Velcro bandage), and the like.

II. Exemplary embodiments

Certain exemplary portable automatic injection devices of the present disclosure are described with reference to Figures 1-10. Certain exemplary needle systems that can be used in exemplary portable automatic injection devices for transporting a therapeutic agent are described with reference to Figures 11-23. Certain exemplary piston drive systems that can be used in exemplary portable automatic injection devices to eject a therapeutic agent from a syringe or cartridge are described with reference to Figures 24-51. Certain exemplary needle protection systems that can be used in exemplary portable automatic injection devices to maintain an injection needle in a retracted position in a post-injection state are described with reference to Figures 52 -55.

The exemplary portable automatic injection devices of the present disclosure may employ a syringe assembly (as illustrated in Figures 1A-1F) or a cartridge assembly (as illustrated in Figures 2A-2F) to contain a dose of a therapeutic agent that can be administered in a patient's body through an injection needle.

Figures 1A-1F illustrate an exemplary embodiment of an automatic portable injection device 100 that includes a syringe assembly that can be used to inject a dose of a therapeutic agent into a patient's body. Figure 1A illustrates a first view from one end and a first side view of the portable device 100 by way of example in a pre-injection packaged state. Figure 1B illustrates the first view from one end and the first side view of the device 100 by way of example in a pre-injection state in which a needle cap covering the injection needle is removed in preparation for an injection. The Figure 1C illustrates the first view from one end and the first side view of the device 100 by way of example during an injection in an injection state in which the patient's skin is pierced by the injection needle. Figure 1D illustrates the first view from one end and the first side view of the device 100 by way of example during an injection in an injection state in which the cylinder portion containing the dose of the therapeutic agent is deployed forward within the housing of the device 100. Figure 1E illustrates the first view from one end and the first side view of the device 100 by way of example during an injection in an injection state in which the cap is actuated by a plunger actuator to eject the dose of the therapeutic agent of the cylinder portion. Figure 1F illustrates the first view from one end and the first side view of the device 100 by way of example after an injection in a post-injection state in which the injection needle retracts into the housing of the device 100.

The portable automatic injection device 100 may include a housing 102. In an exemplary embodiment, the housing 102 may have an elongated configuration, although a person skilled in the art will recognize that the housing 102 may have any size, shape and configuration. suitable for housing a portion of a cylinder that contains a dose of a therapeutic agent to be injected. In an exemplary embodiment, the housing 102 may be formed of any suitable material that includes, but is not limited to, plastic and other known materials.

The housing 102 of the portable automatic injection device 100 may include a layer of adhesive 124 disposed along a portion of contact with the patient at the bottom of the housing 102 that is placed proximal to the patient's skin or a garment of patient clothes. In some exemplary embodiments, the adhesive layer 124 may be configured to be placed on the patient's skin to bind the housing 102 to the patient to administer the dose of the therapeutic agent. The adhesive layer 124 may include a non-adhesive tongue 126 that is not adhesive. The patient can take the non-adhesive tongue 126 and pull it to remove the automatic portable injection device 100 from the skin or the patient's clothing.

Before using the portable automatic injection device 100, for example, in the package state illustrated in Figure 1A, the adhesive layer 124 may be covered by a protective film 128 that preserves the adhesive nature of the adhesive layer 124. The protective film 128 may include a tongue 130 that the patient can take and pull to remove the protective film 128 from the adhesive layer 124. This exposes the adhesive layer 124, allowing the patient to join the housing 102 to his skin. or garment putting the face with the adhesive layer 124 on the skin or the garment.

The housing 102 can accommodate a syringe assembly that extends substantially along a longitudinal L axis between a proximal end (the furthest from the injection needle) and a distal end (the closest to the injection needle). The syringe assembly may include a cylinder portion 106 to contain a dose 108 of a therapeutic agent to be injected into the skin of a patient. The cylinder portion 106 may extend substantially along the longitudinal axis between a proximal end (the furthest from the injection needle) and a distal end (the closest to the injection needle). In an exemplary embodiment, the cylinder portion 106 may be a substantially cylindrical member having a circular cross-section, although a person skilled in the art will recognize that the cylinder portion 106 may have any suitable shape or configuration.

In an exemplary embodiment, the cylinder portion 106 may be stationary within the housing 102 such that the injection process does not result in the movement of the cylinder portion 106 within and with respect to the housing 102. In another exemplary embodiment, the cylinder portion 106 may initially be, that is, prior to an injection in a pre-injection state, in a retracted position toward the proximal end of the device 100 (as illustrated in Figures 1A -1C), and can be operated during an injection in an injection state to an extended position towards the distal end of the device 100.

A plug 110 may be provided at the proximal end of the cylinder portion 106 to seal the dose of the therapeutic agent within the cylinder portion 106 and to apply a force to the dose to expel the dose from the cylinder portion 106. The Cap 110 may be movable within the cylinder portion 106 toward the distal end of the cylinder portion 106 to expel the dose from the cylinder portion 106 during an injection in an injection state. In an exemplary embodiment, the plug 110 may be configured to perform both the sealing functions of the dose and of taking the dose out of the cylinder portion 106. In another exemplary embodiment, a stopper may be provided for sealing the dose within the cylinder portion 106 and a separate piston or piston rod can be provided to confer a force on the cap to take the dose out of the cylinder portion 106.

The syringe assembly may include, at or near its distal end, a syringe cap or a distal portion of the syringe 114 which may include a syringe needle 120 and a needle cover 134 to cover the syringe needle 120. The needle cover 134 it can include a soft needle cap, a rigid needle cap, or both. In an exemplary embodiment, the syringe needle 120 can be aligned parallel to the longitudinal L axis of the device 100. The syringe needle 120 can have any suitable size, shape and configuration suitable for perforating a partition, and is not limited to the illustrative embodiment.

The syringe assembly may include, at or near its proximal end, a piston actuator 112 to selectively drive the plug 110 forward within the cylinder portion 106 toward the distal end to inject the therapeutically effective dose contained in the portion of cylinder 106 in the skin of a patient. The piston actuator 112 may employ an energy storage and controlled energy release mechanism to operate the plug 110. In exemplary embodiments, the piston actuator 112 may be located outside the cylinder portion 106 or partially or completely within the cylinder portion 106. In exemplary embodiments, the plunger actuator 112 can propel the plug 110 directly or indirectly through the use of a plunger disposed between the plug 110 and the plunger actuator 112.

In an exemplary embodiment of the present disclosure, the piston actuator 112 may include a deflection mechanism, for example, a spring, which retracts before injection and is released during injection to drive the plug 110 toward forward within the cylinder portion 106. In another exemplary embodiment, the piston actuator 112 may include a chemical gas generator, for example, an expansion foam, which is in an unexpanded phase before injection and which expands during injection to ^{drive the plug 110 forward into the cylinder portion} 106 ^{. In other exemplary embodiments,} the piston actuator 112 may employ hydraulic working fluid pressure, compressed gas gas pressure, osmotic pressure, hydrogel expansion, and the like.

In an exemplary embodiment of the present disclosure, the piston actuator 112 may move forward within the cylinder portion 106 in a substantially linear manner, that is, substantially constant speed. This may allow the dose to be administered to the patient at a substantially constant rate of administration. The piston actuator 112 may include or be coupled to a damping mechanism that can be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during the release of energy by the actuator. of piston 112. The controlled release of energy can result in a substantially linear administration profile, that is, a substantially constant rate of dose administration over time, and can prevent abrupt changes in the rate of administration. In an exemplary embodiment, a piston actuator 112 may employ the hydraulic pressure of a working fluid and a damping mechanism may employ a flow limiter placed in a fluid path between the working fluid and the plug 110. In another exemplary embodiment, a piston actuator 112 may employ a deflection mechanism and a damping mechanism may employ a viscous damper, a Swiss anchor escape, an out of control leakage, and the like. In another exemplary embodiment, a piston actuator 112 may employ a stepper motor connected to a gear drive system to provide a constant linear management profile.

The housing 102 of the portable automatic injection device 100 can also accommodate an injection button 116 that carries a hollow hypodermic injection needle 118 that is configured to pierce the patient's skin. In an exemplary embodiment, the injection needle 118 can be orthogonally aligned to the longitudinal L axis of the device 100. In an exemplary embodiment, the injection needle 118 can be held in place by an injection needle holder ( not shown) provided on the injection button 116 or separately from the injection button 116. The injection needle 118 may have any suitable size, shape and configuration suitable for piercing the patient's skin to administer the therapeutic agent, and not It is limited to the illustrative embodiment. Suitable needles may have a configured or selected length to provide a suitable injection depth for the desired therapy. Subcutaneous injections normally penetrate approximately six to ten millimeters in the skin. In an exemplary embodiment, the injection needle 118 may have a length of approximately twelve mm and may be injected to a depth of approximately seven mm into the skin. In other exemplary embodiments, injection needle 118 may have lengths suitable for intradermal, other subcutaneous, or intramuscular therapies. Suitable injection needles may have a suitable wall thickness to provide sufficient resistance to the mechanism, a suitable diameter to allow a desired flow rate of the injected substance, while minimizing the patient's feeling, and a tip geometry suitable for the desired therapy while minimizing patient feeling. Suitable injection needles can be coated as needed to minimize patient feeling as allowed by therapy. The injection needle 118 can be covered and maintained in an aseptic condition, that is, sterile condition, by a needle cover 122, for example, a rigid needle cap, a soft needle cap, or both.

The injection button 116 may also include a pierceable partition disposed in the vicinity of the syringe needle 120. In a pre-injection state, the syringe needle 120 does not pierce the partition, thus preventing fluid communication between the cylinder portion 106 and syringe needle 120. In an injection state, when it is pierced by a needle, for example, syringe needle 120, the septum may allow the dose to leave the cylinder portion 106 and enter syringe needle 120 In an exemplary embodiment, one or more covers 115 may enclose the partition in a sterility barrier. Caps 115 can be pierced when syringe needle 120 pierces the septum.

In an exemplary embodiment of the present disclosure, injection needle 118 and syringe needle 120 they can be coupled and in fluid communication with each other by the body of the injection button 116. In another exemplary embodiment, the injection needle 118 and the syringe needle 120 can be coupled and in fluid communication with each other by one or more fluid conduits (not shown). In another exemplary embodiment, the injection needle 118 and the syringe needle 120 can be coupled directly and in fluid communication with each other.

In an exemplary embodiment of the present disclosure, prior to an injection in a pre-injection state, the injection button 116 may be in a vertically raised position with respect to the housing 102 such that the injection button 116 protrudes from the upper part of the housing 102, as illustrated in Figures 1A and 1B. In this position, the injection needle 118 can be retracted into the housing 102 and may not be inserted into the patient's skin. In this position, the syringe needle 120 can be aligned vertically below the septum in the syringe cap 114 and may not pierce the septum. At the beginning of the injection process, the injection button 116 can be pressed down, for example, by a user of the device or automatically. This can push the injection button 116 to a vertically pressed position with respect to the housing 102 closest to the patient's skin so that the injection button 116 no longer protrudes from the top of the housing 102, as illustrated in Figures 1C-1E. In this position, the injection needle 118 can protrude from the housing button 102 and can be inserted into the patient's skin. In this position, the syringe needle 120 can be aligned with the septum in the syringe cap 114 and can pierce the septum.

In an exemplary embodiment of the present disclosure, the septum may initially be separated from the injection button 116. In this embodiment, the syringe needle 120 may pierce the septum when the syringe cap 114 carrying the syringe needle 120 moves inside the housing 102 towards the partition. That is, prior to an injection in a pre-injection state, the syringe needle 120 may be separated from the partition so that there is no fluid communication between the cylinder portion 106 and the injection needle 118 coupled to the injection button 116. In an injection state, the cylinder portion 106 may advance within the housing 102 towards the distal end of the device 100 so that the syringe needle 120 can pierce the septum and establish fluid communication between the cylinder portion 106 and the needle injection 118 coupled to the injection button 116. This fluid communication may allow the dose of the therapeutic agent of the cylinder portion 106 to circulate within the patient's skin through the syringe needle 120 and the injection needle 118 when apply pressure to the dose by the plug 110 during an injection in an injection state.

Referring now to Figure 1F, in an exemplary embodiment, the housing 102 of the portable automatic injection device 100 may include a skin sensing foot 132, which is a structure housed below or in the portion of the proximal housing 102 to the injection site. Before the injection of the therapeutic agent and during the injection, the skin sensing foot 132 is retained inside or forms a portion of the lower part of the housing 102. When the portable automatic injection device 100 joins the injection site and is active, the skin sensor foot 132 may be free to move, but may be restricted by the injection site. When the automatic portable injection device 100 is removed from the injection site, regardless of whether drug administration was completed, the skin sensing foot 132 is no longer restricted, and extends and projects out of the periphery of the housing 102. This, in turn, activates a retraction trigger. When the retraction activator is activated, a retraction mechanism retracts the injection needle 120 which can also raise the injection button 116 from the vertically lowered position to the vertically raised position, so that the injection button 116 protrudes from the upper part of the housing 102 and the injection needle 118 retracts into the housing 102.

Figure 1A illustrates the portable automatic injection device 100 in a pre-injection state, for example, packaging, in which the cylinder portion 106 may be capable of being pre-filled and / or can be pre-filled with the dose 108 of the therapeutic agent and in a retracted position ready for use. The cylinder portion 106 may contain the dose 108 of the therapeutic agent in the defined interior space between the wall or walls of the cylinder portion 106 and the plug 110. In one embodiment, the plunger actuator 112 may store energy which, when releases, the plug 110 can be operated. The injection button 116 may be partially disposed within the housing 102 in the vertically raised position above the injection site, and the injection needle 118 can be retracted within the housing 102. The extrusion of the injection button 116 outside the upper part of the housing 102 can provide a visual indication to the patient that the portable automatic injection device 100 is not in operation.

Figure 1B illustrates the portable automatic injection device 100 in a pre-injection state in which the needle cover 122 and the septum lid are removed. In exemplary embodiments, the protective film 128 may include a connecting member that connects to the needle cover 122, the septum and the needle cover of the syringe in the syringe cap 114. The connecting member may include a strap or other mechanism of Connection. When the protective film 128 is removed, the connecting member of the protective film 128 can remove the needle cover 122 and the septum and the needle cover of the syringe in the syringe cap 114.

Figure 1C illustrates the portable automatic injection device 100 during an injection in an injection state in which the injection button 116 is in the vertically lowered position within the housing 102. In in the vertically lowered position, the injection button 116 may be disposed within the housing 102 in a pulsed or vertically lowered location above the injection site, and the injection needle 118 can be projected from the housing button 102 through of an opening in the housing 102 so that the skin can penetrate the injection site. In the vertically lowered state, the injection button 116 may not protrude from the top of the housing 102, which can provide a visual indication to the patient that the portable portable injection device 100 is in operation.

Figure 1D illustrates the portable automatic injection device 100 during an injection in an injection state in which the cylinder portion 106 containing the dose 108 of the therapeutic agent is deployed forward from a retracted position to an extended position within the device housing 100. The advance of the cylinder portion 106 may carry the distal end of the cylinder portion 106 or the syringe cap 114 in the vicinity of or in contact with the injection button 116. In a mode embodiment For example, the syringe needle 120 may pierce the septum contained in the syringe cap 114 to establish fluid communication between the cylinder portion 106 and the injection needle 118.

Figure 1E illustrates the portable automatic injection device 100 during an injection in an injection state in which the plunger actuator 112 is activated to move the plug 110. The activation of the plunger actuator 112 can release the energy stored in the actuator of piston 112 to move the plug 110 within the cylinder portion 106 toward the distal end of the device 100. The movement of the plug 110 can expel ^{the dose of the therapeutic agent from the cylinder portion} 106 ^{through the distal end of the portion of cylinder 106.} Any suitable mechanism can be used to activate the piston actuator 112 that includes, but is not limited to, a connector member that engages and activates by the depression of the injection button 116 or by the removal of the needle cover 122, a Activator button that can be used by the user, and the like.

Figure 1F illustrates the portable portable injection device 100 after an injection in a post-injection state, for example, after injecting a therapeutically effective dose of the therapeutic agent or the withdrawal of the portable portable injection device 100 from the patient before administration. of a therapeutically effective dose of the therapeutic agent, in which the injection button 116 is in the vertically raised position. In the vertically raised position, the injection button 116 may be partially disposed within the housing 102 at an elevated or vertically raised location above the injection site, and the injection needle 118 can be retracted into the housing 102. A Injection button portion 116 may be projected from the top of the housing 102 to provide a visual indication to the patient that the portable automatic injection device assembly 100 is not in operation (i.e., in a post injection state). The cylinder portion 106 may be empty of the therapeutic agent and the piston actuator 112 may no longer store energy. A skin sensor foot 132 can be extended from the housing button 102 after removal of the device 100 from the injection site.

The housing 102 may include a retraction mechanism that automatically raises the injection button 116 from the vertically lowered state of injection (shown in Figures 1C-1E) to the post-injection state vertically raised (shown in Figure 1F). In an exemplary embodiment, the retraction mechanism may include a deflection mechanism, for example, a spring, which deflects the syringe assembly away from the injection site when the retraction mechanism is activated.

A retraction trigger, when activated, can activate the retraction mechanism to raise the injection button 116 from the vertically lowered state to the vertically raised state. In an exemplary embodiment, the plug 110 and / or the piston actuator 112 may include a connector member connected to the retraction activator. The connecting member may include a strap or other connection mechanism. The connecting member may be of a suitable length such that, when the plug 110 has moved to the end of the cylinder portion 106 (administering a full dose), the connecting member activates a latch which in turn activates the activator of retraction In another exemplary embodiment, the extension of the skin sensing foot 132 from the housing button 102 can activate the retraction activator.

In an exemplary embodiment of the present disclosure, the retraction mechanism may include an end-of-dose retraction activator that, when activated, activates the retraction mechanism. The end of dose retraction activator can be activated when the therapeutically effective dose of therapeutic agent is administered in the portable automatic injection device. In an exemplary embodiment, the dose-end retraction activator may include a latch, for example, a flexible plastic hook, which is released after drug administration is complete. The retraction mechanism may also include an early withdrawal retraction activator that, when activated, activates the retraction mechanism. The early withdrawal retraction activator can be activated when the automatic portable injection device is removed from the injection site before the therapeutically effective dose of therapeutic agent is fully administered. In an exemplary embodiment, the early withdrawal retraction activator may include a latch, for example, a flexible plastic hook, which is released after removal of the portable automatic injection device 100 from the injection site. The retraction mechanism is sensitive to the activator of the end-of-dose retraction and sensitive to the activator of the early withdrawal retraction to automatically retract the syringe assembly from the injection site.

In an exemplary embodiment of the present disclosure, raising the injection button 116 to the vertically raised position may cause the syringe needle 120 to bend down, thus preventing undesirable reuse of the syringe needle and the automatic portable injection device.

Figures 2A-2F illustrate an exemplary embodiment of an automatic portable injection device 200 that includes a cartridge assembly that can be used to inject a dose of a therapeutic agent into a patient's body. Figure 2A illustrates a first view from one end and a first side view of the portable device 200 by way of example in a pre-injection packaged state. Figure 2B illustrates the first view from one end and the first side view of the device 200 by way of example in a pre-injection state in which a needle cap covering the injection needle is removed in preparation for an injection. Figure 2C illustrates the first view from one end and the first side view of the device 200 by way of example during an injection in an injection state in which the patient's skin is pierced by the injection needle. Figure 2D illustrates the first view from one end and the first side view of the device 200 by way of example during an injection in an injection state in which the cylinder portion containing the dose of the therapeutic agent is deployed forward within the housing of the device 200. Figure 2E illustrates the first view from one end and the first side view of the device 200 by way of example during an injection in an injection state in which the cap is actuated by a plunger actuator to eject the dose of the therapeutic agent of the cylinder portion. Figure 2F illustrates the first view from one end and the first side view of the device 200 by way of example after an injection in a post-injection state in which the injection needle retracts into the housing of the device 200.

The portable automatic injection device 200 may include a housing 202. In an exemplary embodiment, the housing 202 may have an elongated configuration, although a person skilled in the art will recognize that the housing 202 may have any size, shape and configuration. suitable for housing a portion of a cylinder that contains a dose of a therapeutic agent to be injected. In an exemplary embodiment, the housing 202 may be formed of any suitable material that includes, but is not limited to, plastic and other known materials.

The housing 202 of the portable automatic injection device 200 may include a layer of adhesive 224 disposed along a portion of contact with the patient at the bottom of the housing 202 that is placed proximal to the patient's skin or a garment of patient clothes. In some exemplary embodiments, the adhesive layer 224 can be configured to be placed on the patient's skin to attach the housing 202 to the patient to administer the dose of the therapeutic agent. The adhesive layer 224 may include a non-adhesive tongue 226 that is not adhesive. The patient can take the non-adhesive tongue 226 and pull it to remove the automatic portable injection device 200 from the skin or the patient's clothing.

Before using the portable automatic injection device 200, for example, in the package state illustrated in Figure 2A, the adhesive layer 224 can be covered by a protective film 228 that preserves the adhesive nature of the adhesive layer 124. The protective film 228 may include a tongue 230 that the patient can take and pull to remove the protective film 228 from the adhesive layer 224. This exposes the adhesive layer 224, allowing the patient to attach the housing 202 to their skin. or garment putting the face with the layer of adhesive 224 on the skin or the garment.

The housing 202 can accommodate a therapeutic cartridge assembly agent that extends substantially along a longitudinal L axis between a proximal end (the furthest from the injection needle) and a distal end (the closest to the injection needle ). The cartridge assembly may include a portion of cylinder 206 to contain a dose 208 of a therapeutic agent to be injected into the skin of a patient. The cylinder portion 206 can extend substantially along the longitudinal axis between a proximal end (the furthest from the injection needle) and a distal end (the closest to the injection needle). In an exemplary embodiment, the cylinder portion 206 may be a substantially cylindrical member having a circular cross-section, although a person skilled in the art will recognize that the cylinder portion 206 may have any suitable shape or configuration.

In an exemplary embodiment of the present disclosure, the cylinder portion 206 may be stationary within the housing 202 so that the injection process does not result in the movement of the cylinder portion 206 within and with respect to housing 202. In another exemplary embodiment, the cylinder portion 206 may initially be, that is, prior to an injection in a pre-injection state, in a retracted position toward the proximal end of the device 200 (as illustrated in Figures 2A-2C), and can be operated during an injection in an injection state to an extended position towards the distal end of the device 200.

A plug 210 may be provided at the proximal end of the cylinder portion 206 to seal the dose of the therapeutic agent within the cylinder portion 206 and to apply a force to the dose to expel the dose from the cylinder portion 206. The cap 210 may be movable within the cylinder portion 206 towards the distal end of the cylinder portion 206 to expel the dose of the cylinder portion 206 during an injection in a state Injection In an exemplary embodiment, the plug 210 can be configured to perform both the sealing functions of the dose and of taking the dose out of the cylinder portion 206. In another exemplary embodiment, a plug can be provided for sealing the dose within the cylinder portion 206 and a separate piston can be provided to confer a force on the cap to take the dose out of the cylinder portion 206.

The cartridge assembly may include, at or near its proximal end, a piston actuator 212 to selectively drive the plug 210 forward within the cylinder portion 206 toward the distal end to inject the therapeutically effective dose contained in the portion of 206 cylinder in the skin of a patient. The piston actuator 212 may employ an energy storage and controlled energy release mechanism to drive the plug 210. In exemplary embodiments, the piston actuator 212 may be located outside the cylinder portion 206 or partially or completely within the cylinder portion 206. In an exemplary embodiment, the plunger actuator 212 can drive the plug 210 directly or indirectly through the use of a plunger disposed between the plug 210 and the plunger actuator 212.

In an exemplary embodiment of the present disclosure, the piston actuator 212 may include a deflection mechanism, for example, a spring, which retracts before injection and is released during injection to drive the plug 210 toward forward within the cylinder portion 206. In another exemplary embodiment, the piston actuator 212 may include a chemical gas generator, for example, an expansion foam, which is in an unexpanded phase before injection and which expands during injection to ^{drive the plug 210 forward into the cylinder portion} 206 ^{. In other exemplary embodiments,} the piston actuator 212 may employ hydraulic working fluid pressure, compressed gas gas pressure, osmotic pressure, hydrogel expansion, and the like.

In an exemplary embodiment of the present disclosure, the piston actuator 212 may move forward within the cylinder portion 206 in a substantially linear manner, that is, substantially constant speed. This may allow the dose to be administered to the patient at a substantially constant rate of administration. The piston actuator 212 may include or be coupled to a damping mechanism that can be used to absorb energy, for example, an initial energy release, and to provide a more controlled release of energy during the release of energy by the actuator. of piston 212. The controlled release of energy can result in a substantially linear administration profile, that is, a substantially constant rate of dose administration over time, and can prevent abrupt changes in the rate of administration.

In an exemplary embodiment of the present disclosure, a piston actuator 212 may employ one or more fluid circuits containing a working fluid in which the hydraulic pressure of the working fluid applies a force to the plug to move the plug inside the cylinder portion of the cartridge. A damping mechanism may employ a flow limiter placed in the fluid circuit between a source of the working fluid and the plug.

In another exemplary embodiment of the present disclosure, a piston actuator 212 may employ a deflection mechanism, for example, a spiral spring or a helical compression spring. A damping mechanism may employ a viscous damper, a Swiss anchor escape, an out of control leakage, and the like.

In another exemplary embodiment of the present disclosure, a piston actuator 212 may employ a stepper motor connected to a gear drive system to provide a constant linear administration profile.

The cartridge assembly may include, at or near its distal end, a cartridge cap 214 that may include a partition and a lid 215 for the partition. The partition can be a layer of perforable material that is disposed adjacent to the distal end of the cylinder portion 206 to seal the dose in the cylinder portion 206. When intact, the partition can seal the dose within the cylinder portion 206 When pierced by a needle, for example, a syringe needle, the septum may allow the dose to leave the cylinder portion 206 and enter the syringe needle. The partition can be formed of a material that can be pierced by a syringe needle. A cover can be provided to protect the accidental perforation wall by the syringe needle when the device 200 is in the pre-injection state packaged as illustrated in Figure 2A. In an exemplary embodiment, the cap of the cartridge 214 may also include a cap for protectively covering a syringe needle provided in the vicinity of the cap of the cartridge 214, thus preventing accidental perforation of the septum by the syringe needle when the device 200 is in the pre-injection state packaged as illustrated in Figure 2A.

The housing 202 of the portable portable injection device 200 can also accommodate an injection button 216 carrying a hollow hypodermic injection needle 218 that is configured to pierce the patient's skin. In an exemplary embodiment, the injection needle 218 can be orthogonally aligned to the longitudinal L axis of the device 200. In an exemplary embodiment, the injection needle 218 can be held in place. by an injection needle holder (not shown) provided on the injection button 216 or separately from the injection button 216. The injection needle 218 may have any suitable size, shape and configuration suitable for piercing the patient's skin to administer the therapeutic agent, and is not limited to the illustrative embodiment. Suitable needles may have a configured or selected length to provide a suitable injection depth for the desired therapy. Subcutaneous injections normally penetrate approximately six to ten millimeters in the skin. In an exemplary embodiment, the injection needle 218 may have a length of approximately twelve mm and may be injected to a depth of approximately seven mm into the skin. In other exemplary embodiments, the injection needle 218 may have lengths suitable for intradermal, other subcutaneous, or intramuscular therapies. Suitable injection needles may have a suitable wall thickness to provide sufficient resistance to the mechanism, a suitable diameter to allow a desired flow rate of the injected substance, while minimizing the patient's sensation, and a tip geometry suitable for therapy. desired, while minimizing the patient's feeling. Suitable injection needles can be coated as needed to minimize patient sensation as allowed by therapy. The injection needle 218 may be covered and maintained in a septic condition by a needle cover 222, for example, a rigid needle cap, a soft needle cap, or both.

The injection button 216 can also carry a hollow needle syringe 220 configured to pierce the partition and establish fluid communication with the cylinder portion 206. In an exemplary embodiment, the syringe needle 220 can be aligned parallel to the L axis. longitudinal of the device 200. The syringe needle 220 may have any suitable size, shape and configuration suitable for perforating the partition and is not limited to the illustrative embodiment.

In an exemplary embodiment of the present disclosure, the injection needle 218 and the syringe needle 220 can be coupled to and in fluid communication with each other by the body of the injection button 216. In another exemplary embodiment, the injection needle 218 and syringe needle 220 can be coupled to and in fluid communication with each other by one or more fluid conduits (not shown). In another exemplary embodiment, the injection needle 218 and the syringe needle 220 can be coupled directly and in fluid communication with each other.

In an exemplary embodiment of the present disclosure, prior to an injection in a pre-injection state, the injection button 216 may be in a vertically raised position with respect to the housing 202 such that the injection button 216 protrudes from the upper part of the housing 202, as illustrated in Figures 2A and 2B. In this position, the injection needle 218 can be retracted into the housing 202 and may not be inserted into the patient's skin. In this position, the syringe needle 220 can be aligned vertically above the partition in the cap of the cartridge 214 and may not pierce the partition. At the beginning of the injection process, the injection button 216 can be pressed down, for example, by a user of the device or automatically. This can push the injection button 216 to a vertically pressed position with respect to the housing 202 closest to the patient's skin so that the injection button 216 no longer protrudes from the top of the housing 202, as illustrated in Figures 2C-2E. In this position, the injection needle 218 can protrude from the housing button 202 and can be inserted into the patient's skin. In this position, the syringe needle 220 can be aligned with the partition in the cap of the cartridge 214 and can pierce the partition.

In an exemplary embodiment of the present disclosure, the septum may initially be separated from the injection button 216. In this embodiment, the syringe needle 220 may pierce the septum when the cap of the cartridge 214 carrying the septum advances within the housing 202 towards the injection button 216. That is, before an injection in a pre-injection state, the syringe needle 220 may be separated from the partition so that there is no fluid communication between the cylinder portion 206 and the needle of injection 218 coupled to the injection button 216. In an injection state, the cylinder portion 206 can advance inside the housing 202 towards the distal end of the device 200 so that the syringe needle 220 can pierce the septum and establish communication fluid between the cylinder portion 206 and the injection needle 218 coupled to the injection button 216. This fluid communication may allow the age dose Therapeutically circulate the cylinder portion 206 into the patient's skin through the syringe needle 220 and the injection needle 218 when pressure is applied to the dose by the cap 210 during an injection in an injection state.

Referring now to Figure 2F, in an exemplary embodiment, the housing 202 of the portable automatic injection device 200 may include a skin sensing foot 232, which is a structure housed below or in the portion of the proximal housing 202 to the injection site. Before the injection of the therapeutic agent and during the injection, the skin sensing foot 232 is retained within or forms a portion of the lower part of the housing 202. When the portable automatic injection device 200 is attached to the injection site and is activated, the skin sensor foot 232 may be free to move, but may be restricted by the injection site. When the automatic portable injection device 200 is removed from the injection site, regardless of whether drug administration was completed, the skin sensing foot 232 is no longer restricted, and extends and projects out of the periphery of the housing 202. This, in turn, activates a retraction trigger. When the retraction activator is activated, a retraction mechanism retracts the injection needle 220 which can also raise the button of injection 216 from the vertically lowered position to the vertically raised position, so that the injection button 216 protrudes from the top of the housing 202 and the injection needle 218 retracts into the housing 202.

Figure 2A illustrates the portable portable injection device 200 in a pre-injection state, for example, as it is packaged, in which the cylinder portion 206 may be capable of being pre-filled and / or can be pre-filled with the dose 208 of the therapeutic agent and in a retracted position ready for use. The cylinder portion 206 may contain the dose 208 of the therapeutic agent in the defined interior space between the wall or walls of the cylinder portion 206 and the plug 210. In one embodiment, the plunger actuator 212 may store energy which, when releases, the cap 210 can be operated. The injection button 216 may be partially disposed within the housing 202 in the vertically raised position above the injection site, and the injection needle 218 can be retracted within the housing 202. Injection button 216 protrusion outside the top of the housing 202 can provide a visual indication to the patient that the portable automatic injection device 200 is not in operation.

Figure 2B illustrates the portable automatic injection device 200 in a pre-injection state in which the needle cover 222 and the septum cover are removed. In exemplary embodiments, the protective film 228 may include a connector member that connects to the needle cover 222 and the syringe partition and needle covers in the cap of the cartridge 214. The connector member may include a strap or other connection mechanism . When the protective film 228 is removed, the connecting member of the protective film 228 can remove the needle cover 222 and the syringe partition and needle covers in the cartridge cap 214.

Figure 2C illustrates the portable automatic injection device 200 during an injection in an injection state in which the injection button 216 is in the vertically lowered position inside the housing 202. In the vertically lowered position, the injection button 216 it can be arranged inside the housing 202 in a pulsed or vertically lowered location above the injection site, and the injection needle 218 can be projected from the housing button 202 through an opening in the housing 202 so that the skin can penetrate the injection site. In the vertically lowered state, the injection button 216 may not protrude from the top of the housing 202, which can provide a visual indication to the patient that the portable portable injection device 200 is in operation.

Figure 2D illustrates the portable automatic injection device 200 during an injection in an injection state in which the cylinder portion 206 containing the dose 208 of the therapeutic agent is deployed forward from a retracted position to an extended position within the device housing 200. The advance of the cylinder portion 206 may carry the distal end of the cylinder portion 206 or the cartridge cap 214 in the vicinity of or in contact with the injection button 216. In an embodiment by way of For example, the syringe needle 220 can pierce the septum held in the cap of the cartridge 214 to establish fluid communication between the cylinder portion 206 and the injection needle 218.

Figure 2E illustrates the automatic portable injection device 200 during an injection in an injection state in which the plunger actuator 212 is activated to move the plug 210. The activation of the plunger actuator 212 can release the energy stored in the actuator of piston 212 to move the plug 210 within the cylinder portion 206 toward the distal end of the device 200. The movement of the plug 210 can expel ^{the dose of the therapeutic agent from the cylinder portion} 206 ^{through the distal end of the portion of cylinder 206.} Any suitable mechanism can be used to activate the piston actuator 212 which includes, but is not limited to, a connector member that engages and activates by the depression of the injection button 216 or by the removal of the needle cover 222, a Activator button that can be used by the user, and the like.

Figure 2F illustrates the portable portable injection device 200 after an injection in a post-injection state, for example, after injecting a therapeutically effective dose of the therapeutic agent or withdrawal of the portable portable injection device 200 from the patient before administration of a therapeutically effective dose of the therapeutic agent, in which the injection button 216 is in the vertically raised position. In the vertically raised position, the injection button 216 may be partially disposed within the housing 202 in an elevated or vertically raised location above the injection site, and the injection needle 218 can be retracted within the housing 202. A Injection button portion 216 can be projected from the top of the housing 202 to provide a visual indication to the patient that the portable automatic injection device assembly 200 is not in operation (i.e., in a post injection state). The cylinder portion 206 may be empty of the therapeutic agent and the piston actuator 212 may no longer store energy. A skin sensor foot 232 can be extended from the housing button 202 after removal of the device 200 from the injection site.

The housing 202 may include a retraction mechanism that automatically raises the injection button 216 from the vertically lowered state of injection (shown in Figures 2C-2E) to the vertically raised state post-injection (shown in Figure 2F). In an exemplary embodiment, the retraction mechanism may include a deflection mechanism, for example, a spring, which deflects the cartridge assembly away from the injection site when the retraction mechanism is activated.

A retraction trigger, when activated, can activate the retraction mechanism to raise the injection button 216 from the vertically lowered state to the vertically raised state. In an exemplary embodiment, the plug 210 and / or the piston actuator 212 may include a connector member connected to the retraction activator. The connecting member may include a strap or other connection mechanism. The connecting member may be of a suitable length such that, when the plug 210 has moved to the end of the cylinder portion 206 (administering a full dose), the connecting member activates a latch which in turn activates the activator of retraction In another exemplary embodiment, the extension of the skin sensing foot 232 from the housing button 202 can activate the retraction activator.

In an exemplary embodiment of the present disclosure, the retraction mechanism may include an end-of-dose retraction activator that, when activated, activates the retraction mechanism. The end of dose retraction activator can be activated when the therapeutically effective dose of therapeutic agent is administered in the portable automatic injection device. In an exemplary embodiment, the dose-end retraction activator may include a latch, for example, a flexible plastic hook, which is released after drug administration is complete. The retraction mechanism may also include an early withdrawal retraction activator that, when activated, activates the retraction mechanism. The early withdrawal retraction activator can be activated when the automatic portable injection device is removed from the injection site before the therapeutically effective dose of therapeutic agent is fully administered. In an exemplary embodiment, the early withdrawal retraction activator may include a latch, for example, a flexible plastic hook, which is released after removal of the portable automatic injection device 200 from the injection site. The retraction mechanism is sensitive to the activator of the end-of-dose retraction and sensitive to the activator of the early withdrawal retraction to automatically retract the cartridge assembly from the injection site.

In exemplary embodiments of the present disclosure, the cylinder portion of the portable automatic injection device 100 (in Figure 1) / 200 (in Figure 2) may be capable of being preloaded and / or can be preloaded with any volume of a therapeutic agent, for example, a therapeutic antibody, desired for intradermal, subcutaneous or intramuscular injections. In an exemplary embodiment, the cylinder portion 106 may be capable of being preloaded and / or can be preloaded with a volume of between about 0.1 milliliters and about 1.0 milliliters, although exemplary devices may not They are limited to this range by way of example of therapeutic agent volumes.

In exemplary embodiments of the present disclosure, the automatic portable injection device 100 (in Figure 1) / 200 (in Figure 2) can be used to inject a therapeutically effective amount of therapeutic agent for a period of time that It varies from about ten seconds to about twelve hours. Certain other exemplary embodiments provide drive devices and systems that cause the syringe plunger to operate at a slow speed to deliver the therapeutic agent to a patient at a slow speed. Slow exemplary embodiments may administer therapeutic agent volumes of about 0.1 milliliters to about 1 milliliter or more in about five minutes to about thirty minutes, although exemplary administration rates are not limited to this range at example mode.

The exemplary embodiments of the present disclosure may provide a linear administration profile for the therapeutic agent so that the rate of administration is substantially constant over time. In some cases, a linear administration profile may reduce the discomfort experienced by the patient. In an exemplary embodiment, the therapeutic agent can be administered in a single slow bolus.

The rate of administration of the therapeutic agent may be dependent on the ambient temperature. At room temperature, that is, approximately 72 ° F (22.2 ° C), the accuracy of the administration time may vary between approximately three percent and approximately ten percent.

Exemplary dimensions of exemplary devices are described with reference to Tables 1 6. However, a person skilled in the art will recognize that exemplary dimensions are provided for illustrative purposes, and that automatic devices Injection by way of example are not limited to the illustrative dimensions.

In an exemplary embodiment of the present disclosure, an automatic portable injection device may have an exemplary length of approximately 4.37 inches (11.1 cm), an exemplary width of approximately 2.12 inches (5.38 cm) and an exemplary height of approximately 1.25 inches (3.17 cm). In an exemplary embodiment, the diameter of the cylinder portion is approximately 1,470 inches (3.73 cm) and the length of the cylinder portion is approximately 2,520 inches (6.40 cm). Tables 1-3 summarize the components of length, width and height, respectively, for two types by way of example of the device by way of example.

Table 1: Summary of length components an example device, inches (cm)

continuation

Table ^ 2: mri m nn l n h r n iiv m m l l (cm)

Tab cm)

In an exemplary embodiment of the present disclosure, the diameter of the cylinder portion in production can be increased from approximately 1,470 inches (3.73 cm) to approximately 0.125 inches (0.32 cm), and the length of the Cylinder portion can be decreased in production from approximately 2,520 inches (6.40 cm) to approximately 0.732 inches (1.86 cm). Tables 4-6 summarize the length, width and height components, respectively, for two exemplary types of the device by way of example.

Table (cm)

Table ^: mri m nn l n h r n iiv m ^ m l l (cm)

Table 6: m ri m n n l l r n iiv m m l l m

Figure 3 is a flow chart of an exemplary method 300 of assembling an automatic injection device 100 by way of example. In step 302, a syringe or cartridge assembly can be sterilized and assembled. In step 304, an injection button can be sterilized and assembled. In step 306, the cylinder portion of the syringe or cartridge assembly can be loaded with a dose of a therapeutic agent to be administered to a patient. In step 308, a sterile plug can be placed in the portion of the syringe or cartridge assembly cylinder to seal the therapeutic agent within the cylinder portion. Containment of the therapeutic agent within the automatic portable injection device by the sterile cylinder portion and the sterile cap maintains the sterility of the therapeutic agent. As such, in an exemplary embodiment, the remaining components of the portable automatic injection device can be assembled in a non-sterile environment after the cylinder portion is prechargeable and / or preloaded with the therapeutic agent. For example, in step 310, a non-sterile plunger actuator, for example, a deflection mechanism, can be inserted behind the plug.

In step 312, the syringe or cartridge assembly can be inserted into a non-sterile housing. The housing can be pre-assembled with other non-sterile components, for example, an adhesive layer, a protective film, a skin sensing foot, and the like. In step 314, the injection button (with a sterile fluid path enclosed and one or more needles) can be inserted into the non-sterile housing. In exemplary embodiments, the cylinder portion, the enclosed hypodermic injection needle, the syringe needle, the needle cover and the cap can provide the sterility barrier for the therapeutic agent and the flow path. Thus, once the cylinder portion is loaded with the therapeutic agent and the cap is inserted into the cylinder portion, the assembly of the remaining portions of the device does not require aseptic conditions. No need to perform therapeutic agent transfer steps by the user. In step 316, the assembled automatic injection device can be placed in a total wrap, if necessary, and then can be commercially packaged for sale. Figure 1A illustrates an exemplary embodiment of the automatic injection device assembled in the pre-injection packaged state.

Figure 4 is a flow chart of an exemplary method 400 using an automatic injection device as an example. The automatic portable injection device packaged and prechargeable and / or preloaded with a therapeutic agent can generally be stored in refrigerated storage before use. In step 402, the automatic packaged injection device can be removed from storage. In step 404, the automatic portable injection device can be removed from its container and any total wrap, and heated to room temperature, for example, by leaving the portable device out of the container at room temperature or by heating the portable device. In step 406, the patient can confirm that the cylinder portion contains a volume of the therapeutic agent through an inspection window of the therapeutic agent disposed in the device housing, and can also confirm the clarity of the therapeutic agent, if necessary .

In step 408, the injection site on the patient's skin can be selected and prepared for administration of the therapeutic agent. In step 410, the patient uses the portable automatic injection device to inject the therapeutic agent into the injection site. The steps generally involved within step 410 are described below with respect to Figure 5. In step 412, after performing the injection, the portable automatic injection device can be removed from the patient and disposed of in an appropriate manner.

Figure 5 is a flow chart of an exemplary method 500 using an automatic injection device by way of example to inject a therapeutically effective amount of a therapeutic agent into a patient. The exemplary method 500 is a detailed summary of step 410 in Figure 4. In step 502, the patient removes the protective film that covers and protects the adhesive layer of the portable automatic injection device. In some exemplary embodiments, removal of the protective film also removes the needle cover and the septum cap in the syringe or cap of the cartridge.

In step 504, the patient applies the patient contact portion of the automatic portable injection device with the adhesive layer to the injection site (or a garment around the injection site) so that the device is retained from Reliable form on the injection site during the injection of the therapeutically effective dose of therapeutic agent.

In step 506, once the portable portable injection device is attached to the injection site, the patient can press the injection button from a vertically raised position in the pre-injection state to a vertically lowered position in the injection state within of the housing. In the vertically raised position, the end of the injection button carrying the injection needle retracts into the housing and is not exposed outside the housing. When pressed, the end of the injection button carrying the injection needle moves down either linearly or rotatably inside the housing so that the injection needle exits an opening in the housing and is exposed. This allows the injection needle to penetrate the patient's skin to an appropriate depth for the injection of the therapeutic agent. The downward movement of the injection button in the housing can be linear (i.e., a vertical downward movement) or rotatable (i.e., in a circular motion around a pivot point).

In an exemplary embodiment of the present disclosure, the injection button is pressed into the housing by the patient by manually pushing the injection button. In another exemplary embodiment, the patient can activate an injection activator, for example, an activator button located in a conveniently accessible location such as the upper part of the housing, which causes the injection activator to automatically press the Injection button on the housing and in turn causes the injection needle to pierce the patient's skin. In an exemplary embodiment, pressing the injection trigger button may release a latch on the injection trigger that allows a spring to divert the injection button down into the housing. The same movement of the injection button may cause the injection needle to be inserted at the injection site to an appropriate depth.

In step 508, pressing the injection button can activate a syringe or cartridge actuator that moves the syringe or cartridge assembly, more specifically, the cylinder portion, forward within and with respect to the housing from a retracted position (in which the distal end of the syringe or cartridge assembly is separated from the injection button) to an extended position (in which the distal end of the syringe or cartridge assembly is adjacent to and / or in contact with the injection button). In another exemplary embodiment, the syringe or cartridge actuator is activated not by pressing the injection button, but by the user activating an activator, for example, in the form of an activating button. In an exemplary embodiment, movement of the syringe or cartridge assembly toward the injection button may cause the syringe needle to pierce the septum.

In step 510, when the distal end of the cylinder portion makes contact with the injection button, the plunger actuator can break the static friction between the plug and the inside of the wall or walls of the cylinder portion and cause The cap moves forward towards the syringe needle on the injection button to administer the therapeutic agent by means of the injection needle. The piston actuator can overcome the static friction of the plug in one stage and activate the plug in a later stage, or the piston actuator can overcome the static friction of the plug and activate the plug simultaneously. The movement of the cap may cause the dose to be released through the syringe needle into the injection needle and thus into the patient's skin.

In an exemplary embodiment of the present disclosure, forward movement of the syringe or cartridge assembly within the housing and forward movement of the cap within the cylinder portion can take place in separate stages. In another exemplary embodiment, the forward movement of the syringe or cartridge assembly inside the housing and the forward movement of the cap within the cylinder portion can take place at the same stage, for example, simultaneously.

The rate of administration of the therapeutic agent may depend on the characteristics of the plunger actuator. The plunger actuator can take the form of several embodiments by way of example. In some exemplary embodiments, the plunger actuator may employ energy storage and release means, for example, deflection mechanisms (including, but not limited to, one or more springs, for example, spiral springs or springs helical compression), compressed gases, chemical gas generators (such as expanding foams), osmotic pressure, hydrogel expansion, etc. A damping or control mechanism (including, but not limited to, a viscous damper or an exhaust) may be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during the energy release by the plunger actuator. A flow restrictor placed in a fluid path between the needle and the cap can be used to further regulate the rate of administration of the therapeutic agent, for example, where the plunger actuator supplies an unrestricted spring force through a working fluid. . Thus, an appropriate piston actuator and an appropriate control mechanism can be selected to administer the dose at a controlled rate, for example, in a single slow bolus free of or substantially free of any burning sensation to the patient.

In an exemplary embodiment, pressing the injection button may damage the retraction mechanism which, when activated, retracts the injection button into the housing 102 after an injection in a post injection state.

In step 512, after administration of the therapeutically effective dose, the stopper and / or the plunger actuator can activate the end of dose retraction activator of the retraction mechanism. The plug and / or the plunger actuator may include a connector member connected to the activator of the end of dose retraction. The connecting member may include a strap or other connection mechanism. The connecting member may be of a suitable length such that, when the cap has moved to the end of the syringe or cartridge assembly (administering a full dose), the connecting member activates a latch which in turn activates the activator of retraction

In step 514, once the dose-end retraction activator is activated, the retraction mechanism can retract the injection button up into the housing and away from the patient contact portion so that the assembly of syringe or cartridge enters a post-injection state. In an exemplary embodiment, the movement of the injection button from the injection state to the post-injection state creates an audible sound, for example, a "click", which provides an auditory indication of the end of the administration of the therapeutic agent. Once retracted, the injection button protrudes out of the housing, which provides a visual indication of the state of the portable automatic injection device, for example, end of administration of the therapeutic agent or a visual indication of the device in the post-injection state .

However, if the portable device is removed from the patient's skin before the dose is finished therapeutically Effective of the therapeutic agent, the skin sensing foot can be extended outside the housing and activate the early withdrawal retraction activator of the retraction mechanism. Once the early withdrawal retraction activator is activated, the retraction mechanism deploys the injection button up in the housing away from the patient contact portion so that the syringe or cartridge assembly enters a state post injection In an exemplary embodiment, the plunger actuator may continue to move forward in the cylinder portion toward the syringe needle when the device is removed from the patient before the end of administration of a therapeutically effective dose of the therapeutic agent.

In step 516, after retraction, a needle lock is coupled with the injection needle to prevent refolding of the injection needle to provide puncture protection. The needle lock may be a member that prevents the injection needle from leaving the housing once attached, and can be located in the housing near the injection needle. Exemplary needle locking may include, but is not limited to, a plastic plate, a metal plate, a clip, etc.

Figures 6A-6C illustrate an exemplary embodiment of an automatic portable injection device 600 suitable for linear insertion of a needle into a patient's skin. By linear insertion, the end of a cartridge assembly carrying a needle descends linearly into a housing of the portable automatic injection device so that the needle is inserted into the patient. More specifically, Figure 6A illustrates the exemplary portable device in a pre-injection state, for example, as packaged; Figure 6B illustrates the exemplary portable device in an injection state just before, while or just after injecting a therapeutic agent into a patient; and Figure 6C illustrates the exemplary portable device in a post-injection state after the administration of the therapeutic agent within the patient or withdrawn from the patient before completing the administration of the therapeutic agent.

The portable portable injection device 600 includes a housing 635 to accommodate a therapeutic agent cartridge assembly 610, which contains a dose of a therapeutic agent to be injected subcutaneously into a patient. In an exemplary embodiment, the exterior of the therapeutic agent cartridge assembly 610 may be provided with one or more roughnesses, and the interior of the housing 635 may be provided with one or more grooves or channels that provide a smooth path for the roughness of the cartridge assembly 610 as the cartridge assembly moves inside the housing 635. The one or more roughnesses on the outside of the cartridge assembly 610 can take the form of desired lines on the cartridge assembly 610. The one or more grooves or channels on the inside of the housing 635 may take the form of sunken U-shaped or watering hole lines. The upper portion of the grooves or channels may be open, so that the roughnesses can slide in and out of the upper portion of the grooves or channels. In the linear insertion embodiment illustrated in Figures 6A-6C, the roughnesses and grooves / channels may be straight lines. In the rotary insertion embodiment illustrated in Figures 7A-7C, the roughnesses and grooves / channels may be lines that are curved around the center of rotation, that is, the pivot point of the cartridge assembly 610.

In another exemplary embodiment of the present disclosure, the exterior of the cartridge assembly 610 may have no roughness, and the interior of the housing 635 may have no groove or channel.

The housing 635 preferably has an elongated configuration, although a person skilled in the art will recognize that the housing 635 can have any size, shape and configuration suitable to accommodate a hypodermic needle that can be coupled to a cylinder portion of a therapeutic agent that is going to inject The housing 635 can be formed of any suitable material that includes, but is not limited to, plastic and other known materials. In another embodiment, the therapeutic agent cartridge 610 may be formed of any compatible material suitable for sterilization that includes, but is not limited to, glass and other known materials. The housing 635 includes an adhesive layer 640 disposed along a patient contact portion of the housing 635 that is placed proximal to the patient's skin or a patient's clothing. In some embodiments, the adhesive layer 640 is configured to be placed on the patient's skin to attach the housing 635 to the patient to administer a therapeutic agent. Adhesive layer 640 includes a non-adhesive tongue 645 that is not adhesive. The patient can take the non-adhesive tongue 645 and pull it to remove the adhesive layer 640 and thus the automatic portable injection device 600 from the skin or the patient's clothing.

Before using the portable automatic injection device 600, for example, in the pre-injection state, the adhesive layer 640 is covered by a protective film 650 that preserves the adhesive nature of the adhesive layer 640. The protective film 650 can include a tab 655 that the patient can take and pull away to remove the protective film 650 from the adhesive layer 640. This exposes the adhesive layer 640, allowing the patient to attach the shell 635 to their skin or clothing by putting the face with the layer of adhesive 640 on the skin or the garment.

In exemplary embodiments of the present disclosure, protective film 650 (in Figure 6A) / 750 (in Figure 7A) may include a connector member that is connected to the plunger actuator 630 (in Figure 6A) / 730 (in Figure 7A). The connecting member may include a strap or other connection mechanism.

When protective film 650 (in Figure 6A) / 750 (in Figure 7A) is removed, the connecting member of protective film 650 (in Figure 6A) / 750 (in Figure 7A) releases static friction between the plug 615 (in Figure 6A) / 715 (in Figure 7A) and the inner wall of cylinder 605 (in Figure 6A) / 705 (in Figure 7A), and activates the piston actuator 630 (in Figure 6A) / 730 (in Figure 7A).

The therapeutic agent cartridge assembly 610 may include a hollow portion of cylinder 605 to contain a therapeutically effective dose of the therapeutic agent to be injected. The illustrative cylinder portion 605 is substantially cylindrical in shape, although a person skilled in the art will recognize that the cylinder portion 605 can have any suitable shape or configuration. A cap 615 seals the dose of therapeutic agent within the cylinder portion 605.

The therapeutic agent cartridge assembly 610 may also include a hollow hypodermic needle 625 connectable to or connected to, and in fluid communication with, the cylinder portion 605, through which the dose can be expelled by applying pressure to the cap 615. Needle 625 may have any suitable size, shape and configuration suitable for piercing the patient's skin to administer the therapeutic agent subcutaneously, and is not limited to the illustrative embodiment. Suitable needles may have a configured or selected length to provide a suitable injection depth for the desired therapy. Subcutaneous injections normally penetrate approximately six to ten millimeters in the skin. In an exemplary embodiment, the needle 625 can have a length of approximately twelve mm and can be injected to a depth of approximately seven mm into the skin. In other exemplary embodiments, the needle 625 may have lengths suitable for intradermal, other subcutaneous, or intramuscular therapies. Suitable needles may have a suitable wall thickness to provide sufficient resistance to the mechanism, a suitable diameter to allow a desired flow rate of the injected substance, while minimizing the patient's sensation, and a tip geometry suitable for the desired therapy, while minimizing the patient's feeling. Suitable needles may be coated as needed to minimize the patient's feeling as allowed by therapy. Needle 625 can be covered and maintained in a septic condition by a soft and rigid needle cap assembly 620.

In the exemplary embodiment of the present disclosure illustrated in Figures 6A-6C, the needle 625 projects substantially at a right angle to the longitudinal axis of the portable device 600. In this exemplary embodiment, the cylinder portion 605 includes an elbow 607 that substantially extends a right angle to the longitudinal axis of the device 600. In this embodiment, the needle 625 is connected to the elbow 607.

The portable portable injection device 600 may include a piston actuator 630 to selectively drive the plug 615 forward towards the distal end of the therapeutic agent cartridge assembly 610 to inject the therapeutically effective dose contained in the cylinder portion 605 into the patient. . The piston actuator 630 may employ an energy storage and controlled release energy mechanism to operate the plug 615. In an exemplary embodiment, the piston actuator 630 may include a deflection mechanism, for example, a spring , which is retracted before injection and released during injection to drive the plug 615 forward in the cylinder portion 605. In another exemplary embodiment, the piston actuator 630 may include a chemical gas generator, for example, an expansion foam, which is in an unexpanded phase before injection and which expands during injection to drive the plug 615 forward in the cylinder portion 605 towards the distal end of the therapeutic agent cartridge assembly 610. In other exemplary embodiments, the piston actuator 630 may employ compressed gases, osmotic pressure, hydrogel expansion, etc. A damping mechanism can be used to absorb energy, for example, an initial release of energy, and to provide a controlled release of energy during energy release by the plunger actuator 630 (in Figure 6A) / 730 (in the Figure 7A). A flow restrictor placed in a fluid path between the needle and the cap 615 (in Figure 6A) / 715 (in Figure 7A) can be used to further regulate the rate of administration of the therapeutic agent, for example, where the Piston actuator 630 (in Figure 6A) / 730 (in Figure 7A) supplies an unrestricted spring force.

In an exemplary embodiment of the present disclosure, the piston actuator 630 can be advanced forward within the cylinder portion 605 in a constant linear motion. Any number of mechanisms, internal or external to the automatic portable injection device 600, can be used to provide a constant linear motion that includes, but is not limited to, a stepper motor connected to a gear drive system. Other exemplary mechanisms for providing substantially constant linear motion in a controlled mode are described with reference to Figures 24-45.

The plug 615 (in Figure 6A) / 715 (in Figure 7A) and / or the piston actuator 630 (in Figure 6A) / 730 (in Figure 7A) may include a connector member connected to the retraction activator . The connecting member may include a strap or other connection mechanism. The connecting member may be of a suitable length so that, when the plug 615 (in Figure 6A) / 715 (in Figure 7A) has moved to the end of the cartridge assembly 610 (in Figure 6A) / 710 (in Figure 7A) (administering a full dose), the connecting member activates a latch which in turn activates the retraction activator.

Referring now to Figure 6C, in an exemplary embodiment, the housing 635 includes a skin sensing foot 660, which is a structure housed below or in the portion of the housing 635 proximal to the injection site. Prior to injection of the therapeutic agent and during injection, the skin sensing foot 660 is retained within or forms a portion of the bottom of the housing 635. When the portable automatic injection device 600 is attached to the injection site and is activated, the 660 skin sensor foot may be free to move, but may be restricted by the injection site. When the automatic portable injection device 600 is removed from the injection site, regardless of whether drug administration was completed, the skin sensing foot 660 is no longer restricted, and extends and projects out of the periphery of the housing 635. This, in turn, activates the withdrawal retraction trigger.

Figure 6A illustrates the automatic portable injection device 600 in a pre-injection state, for example, as it is packaged and ready for use or as ready for packaging. The device 600 may include a pre-filled and / or pre-filled syringe or cartridge assembly. In an exemplary embodiment, in a pre-injection state, the syringe or cartridge assembly may be in a retracted position ready for use. In the ^{pre-injection state, the therapeutic agent cartridge assembly} 610 ^{is partially disposed within the} housing 635 at an elevated distal location of the injection site, and the needle 625 retracts within the housing 635. Visual indications to the patient of that the portable portable injection device 600 is not in operation may include a portion of the therapeutic agent cartridge assembly 610 that projects out of the housing 635 in the pre-injection state. The cylinder portion 605 contains a dose of a therapeutic agent that is contained by the defined interior space between the wall or walls of the cylinder portion 605 and the cap 615. In one embodiment, the plunger actuator 630 stores energy.

Figure 6B illustrates the portable automatic injection device 600 in an injection state ready to inject, inject or just after injecting a therapeutically effective dose of a therapeutic agent, in which the therapeutic agent cartridge assembly 610 is in a position. pressed. In the pulsed position, the therapeutic agent cartridge assembly 610 is disposed within the housing 635 in a pulsed location proximal to the injection site, and the needle 625 projects out of the housing 635 through an opening in the housing 635 so that the skin can penetrate the injection site. In the injection state, the therapeutic agent cartridge assembly 610 is not projected out of the housing 635 to provide a visual indication to the patient that the portable portable injection device 600 is in operation. The piston actuator 630 releases its stored energy to drive the plug 615. This cooperative movement of the piston actuator 630 and the plug 615 expels the therapeutic agent in the cylinder portion 605 out through the needle 625.

Figure 6C illustrates the automatic portable injection device 600 in a post-injection state, for example, after injecting a therapeutically effective dose of the therapeutic agent or withdrawing the automatic portable injection device 600 from the patient before administering a therapeutically dose. effective of the therapeutic agent, in which the therapeutic agent cartridge assembly 610 is in a retracted position. In the retracted position, the therapeutic agent cartridge assembly 610 is disposed within the housing 635 at an elevated location distal to the injection site, and the needle 625 retracts within the housing 635. A portion of the agent cartridge assembly Therapeutic 610 is projected out of the housing 635 to provide a visual indication to the patient that the assembly of portable automatic injection device 600 is not in operation (ie, in a post-injection state). The cylinder portion 605 may be empty of the therapeutic agent, and the plunger actuator 630 may no longer store energy.

The housing 635 includes a retraction mechanism that automatically raises the therapeutic agent cartridge assembly 610 from the injection state (pulsed position shown in Figure 6B) to the post-injection state (retracted position shown in Figure 6C). In an exemplary embodiment, the retraction mechanism may include a deflection mechanism, for example, a spring, which deflects the cartridge assembly away from the injection site when the retraction mechanism is activated.

The retraction mechanism includes an end-of-dose retraction activator that, when activated, activates the retraction mechanism. The end of dose retraction activator is activated when the therapeutically effective dose of therapeutic agent is administered in the portable automatic injection device. In an exemplary embodiment, the dose-end retraction activator may include a latch, for example, a flexible plastic hook, which is released after drug administration is complete. The retraction mechanism also includes an early withdrawal retraction activator that, when activated, activates the retraction mechanism. The early withdrawal retraction activator is activated when the automatic portable injection device is removed from the injection site before the therapeutically effective dose of therapeutic agent is fully administered. In an exemplary embodiment, the early withdrawal retraction activator may include a latch, for example, a flexible plastic hook, which is released after removal of the portable automatic injection device 600 from the injection site. The retraction mechanism is sensitive to the activator of the end-of-dose retraction and sensitive to the activator of the early withdrawal retraction to automatically retract the cartridge assembly from the injection site.

Figures 7A-7C illustrate an exemplary embodiment of an automatic portable injection device 700 suitable for rotating needle insertion in a patient's skin. In the rotary insert, the end of a therapeutic agent cartridge assembly 710 carrying the needle 725 descends in a rotating mode around a pivoting point to insert the needle 725 into the patient's skin. More specifically, Figure 7A illustrates the exemplary portable device in a pre-injection state, for example, as it is packaged with a previously loaded and curved sterile hypodermic needle and cylinder portion containing a therapeutic agent; Figure 7B illustrates the exemplary portable device while in an injection state just before, while or just after injecting a therapeutic agent into a patient; and Figure 7C illustrates the exemplary portable device in a post-injection state after administration of the therapeutic agent within the patient or removal of the portable device from the patient before the end of the administration of the therapeutic agent to the patient.

The therapeutic agent cartridge assembly 710 is rotatably movable within the housing 735 around a pivoting point 765 in the housing. In an exemplary embodiment, the exterior of the therapeutic agent cartridge assembly 710 may be provided with one or more roughnesses, and the interior of the housing 735 may be provided with one or more grooves or channels that provide a path for the roughness of the cartridge 710 as the cartridge moves inside the housing 735 between the various states. In another exemplary embodiment, the exterior of the cartridge assembly 710 is free of roughness, and the interior of the housing 735 is free of grooves or channels.

When the therapeutic agent cartridge assembly 710 is pressed into the housing 735, the therapeutic agent cartridge assembly 710 is rotatably moved downward about the pivoting point 765 so that the needle 725 is exposed and penetrates the patient's skin. In this exemplary embodiment, the needle 725 penetrates the patient's skin with a 90 ° angle shift. Similarly, when the therapeutic agent cartridge assembly 710 is retracted, the therapeutic agent cartridge assembly 710 swivels upwardly around pivot point 765 so that the needle 725 retracts into the housing 735. The mechanism to implement This rotational movement of the therapeutic agent cartridge assembly 710 may be simpler and more robust than the mechanism required for the linear insertion of Figures 6A-6C.

The needle 725 is curved, with a radius defined by the pivot point 765 and the distance of the needle 715 to the pivot point 765 along the longitudinal axis of the housing 735. The curvature of the needle 725 increases patient comfort during Needle insertion The needle 725 may be preferentially oriented with the sharp point of the needle closest to the pivot point 765.

The features in Figures 7A-7C similar to those illustrated in Figures 6A-6C are described above with respect to Figures 6A-6C.

In exemplary embodiments of the present disclosure, the therapeutic agent cartridge assembly 610 and 720 of Figures 6A-6C and 7A-7C, respectively, may be capable of being preloaded and / or can be preloaded with any volume of a therapeutic agent, for example, a therapeutic antibody, desired for intradermal, subcutaneous or intramuscular injections. In an exemplary embodiment, the cartridge assembly 610 and 720 may be capable of being preloaded and / or can be preloaded with a volume of approximately 0.8-0.85 milliliters, although the example cartridge assemblies they are not limited to these volumes by way of example. In another exemplary embodiment, the cartridge assembly 610 and 720 may be capable of being preloaded and / or may be preloaded with a volume of approximately 1 milliliter or more.

In exemplary embodiments, the portable automatic injection device 600 (in Figure 6A) / 700 (in Figure 7A) can be used to inject the therapeutically effective amount of therapeutic agent over a period of time ranging from about ten seconds to about twelve hours. In an exemplary embodiment, the therapeutic agent can be administered at a fixed rate for an administration time of between about five minutes and about thirty minutes. The automatic portable injection device 600 (in Figure 6A) / 700 (in Figure 7A) can be used to inject a volume of therapeutic agent into a single slow bolus.

The rate of administration of the therapeutic agent may be dependent on the ambient temperature. At room temperature, that is, approximately 72 ° F (22.2 ° C), the accuracy of the administration time may vary between approximately three percent and approximately ten percent.

Figure 8 is a flow chart of an exemplary method 800 of assembling an automatic portable injection device 600 or 700 by way of example. In step 805, the cylinder portion 605/705, the needle 625/725 and the needle cap 620/720 are sterilized. In step 810, the cylinder portion 605/705 is loaded with a dose of the therapeutic agent to be administered to the patient. In step 815, a sterile plug 615/715 is placed in the cylinder portion 605/705 to seal the therapeutic agent within the cylinder portion 605/705. Containment of the therapeutic agent within the portable automatic injection device 600 or 700 by the sterile cylinder portion 605/705, the sterile cap 615/715 and the needle cover 620/720 maintains the sterility of the therapeutic agent and the needle 625 / 725. As such, the remaining components of the automatic injection device Portable can be assembled in a non-sterile environment after the 605/705 cylinder portion is pre-loaded with a therapeutic agent. For example, in step 820, a non-sterile plunger actuator 630/730 is inserted behind the cap 615/715 in the therapeutic agent cartridge assembly 610/710.

In step 825, the therapeutic agent cartridge assembly 610/710 is inserted into a non-sterile 635/735 housing. The 635/735 housing can be pre-assembled with other non-sterile components, for example, the adhesive layer 640/740, the protective film 650/750, the skin sensor foot 660/760. In exemplary embodiments, the cylinder portion 605/705, needle 625/725, needle cap 620/720, and cap 615/715 of the therapeutic agent cartridge assembly 610/710 provide the barrier to sterility for the therapeutic agent and subcutaneous contact surfaces. Thus, once the cylinder portion 605/705 is loaded with the therapeutic agent, the plunger 615/715 is inserted into the cylinder portion 605/705 and the needle cover 620/720 is in place: the assembly of The remaining portions of the 610/710 therapeutic agent cartridge assembly and the 635/735 housing assembly do not require aseptic conditions. No therapeutic agent transfer steps are required by the user. Figures 6A and 7A illustrate exemplary embodiments of the 600/700 portable assembled automatic injection device in a pre-injection state.

In step 830, the 600/700 assembled portable automatic injection device can be placed in a total wrap, if necessary, and then commercially packaged for sale.

Figure 9 is a flow chart of an exemplary method 900 using an automatic injection device 600 or 700 by way of example. The 600/700 portable automatic injection device packaged and preloaded with a therapeutic agent is generally stored in refrigerated storage before use. In step 905, the 600/700 portable packed automatic injection device is taken out of storage. In step 910, the 600/700 portable automatic injection device is removed from its container and any total wrap and heated to room temperature, for example, by leaving the portable device out of the container at room temperature or by heating the portable device. In step 915, the patient confirms that the therapeutic agent cartridge assembly 610/710 includes a volume of the therapeutic agent in the portable device 600/700 through an inspection window of the therapeutic agent disposed in the housing of the portable device, and can also confirm the clarity of the therapeutic agent, if necessary. In step 920, the injection site on the patient's skin is selected and prepared for administration of the therapeutic agent. In step 925, the patient uses the automatic portable injection device 600/700 to inject the therapeutic agent into the injection site. The steps generally involved within step 920 are described below with respect to Figure 10. In step 930, after removing the portable portable injection device 600/700 from the patient, the portable portable injection device 600/700 removed It is disposed of in an appropriate manner.

Figure 10 is a flow chart of an exemplary method 1000 of using an automatic portable injection device 600 or 700 by way of example for injecting a therapeutically effective amount of a therapeutic agent into a patient. Method 1000 by way of example is a detailed summary of step 920 in Figure 9. In step 1005, the patient removes protective film 650/750 that covers and protects the adhesive layer 640/740 of the automatic injection device 600/700 laptop. In some exemplary embodiments, removal of the protective film 650/750 also removes the needle cap 620/720 and exposes the needle 625/725 for injection. In some exemplary embodiments, removal of the protective film 650/750 also breaks the static friction between the plug 615/715 and the inner wall of the cylinder 605/705 and activates the piston actuator 630/730. In exemplary embodiments, protective film 650/750 may include a connector member that is connected to the plunger actuator 630/730. The connecting member may include a strap or other connection mechanism. When the protective film 650/750 is removed, the connecting member of the protective film 650/750 releases static friction between the plug 615/715 and the inner wall of the cylinder 605/705, and activates the piston actuator 630/730.

In step 1010, the patient applies the patient contact portion of the 600/700 portable automatic injection device with the 640/740 adhesive layer to the injection site (or a garment around the injection site) so that the portable device is reliably retained on the injection site during the injection of the therapeutically effective dose of therapeutic agent.

In step 1015, once the portable 600/700 automatic injection device is attached to the injection site, the therapeutic agent cartridge assembly 610/710 descends from a ready position in the pre-injection state to a pulsed position in the injection status inside the 635/735 housing. In the ready position, the end of the 610/710 therapeutic agent cartridge assembly carrying the 625/725 needle retracts into the 635/735 housing and is not exposed outside the housing. When pressed, the end of the 610/710 therapeutic agent cartridge assembly carrying the 625/725 needle moves down either linearly or rotatably within the 635/735 housing such that the 625/725 needle exits a opening in the housing 635/735 and exposed. This allows the needle 625/725 to penetrate the patient's skin to a depth appropriate for injection of the therapeutic agent. The downward movement of the therapeutic agent cartridge assembly 610/710 in the 635/735 housing can be linear (i.e., a vertical downward movement) or rotatable (i.e., in a circular motion around a pivot point). Figures 6B and 7B illustrate exemplary embodiments of the portable automatic injection device 600 and 700 in an injection state with the agent cartridge Therapeutic 610/710 pressed into the 635/735 housing after performing step 1015.

In an exemplary embodiment of the present disclosure, the 610/710 therapeutic agent cartridge assembly is pressed into the 635/735 housing by the patient by manually pushing the 610/710 therapeutic agent cartridge assembly. In another exemplary embodiment, the patient can activate an injection trigger, for example, an insert trigger button located in a conveniently accessible location such as the upper part of the housing 635/735, which causes an actuator of the insertion automatically press the 610/710 therapeutic agent cartridge assembly into the 635/735 housing and in turn, cause the 625/725 needle to pierce the patient's skin. In an exemplary embodiment, pressing the insert activator button can release a latch on the insert activator that allows a spring to deflect the cartridge assembly 610/710 down into the housing 635/735. The same movement of the 610/710 cartridge assembly may cause the 625/725 needle to be inserted into the injection site to an appropriate depth.

In an exemplary embodiment of the present disclosure, pressing the therapeutic agent cartridge assembly 610/710 activates the plunger actuator 630/730 to begin movement of the cap 615/715 to inject the therapeutically effective dose into the patient. The depression of the 610/710 therapeutic agent cartridge assembly causes the 630/730 piston actuator to break the static friction between the 615/715 plug and the inside of the wall or walls of the 605/705 cylinder portion and cause cap 615/715 moves forward toward needle 625/725 in the therapeutic agent cartridge assembly 610/710 to administer the therapeutic agent by needle 625/725. The piston actuator 630/730 can overcome the static friction of the plug at one stage and activate the plug at a later stage, or the piston actuator 630/730 can overcome the static friction of the plug and activate the plug simultaneously. In another exemplary embodiment, the piston actuator 630/730 is activated not by pressing the therapeutic agent cartridge, but by the user activating an injection activator, for example, in the form of an injection activating button.

The rate of administration of the therapeutic agent may depend on the characteristics of the piston actuator 630/730. The piston actuator 630/730 can take the form of several exemplary embodiments. In some exemplary embodiments, the piston actuator 630/730 may employ energy storage and release means, for example, deflection mechanisms (such as springs), compressed gases, chemical gas generators (such as expanding foams) , osmotic pressure, hydrogel expansion, etc. A damping mechanism can be used to absorb energy, for example, an initial energy release, and to provide a more controlled release of energy during energy release by the 630/730 piston actuator. A flow limiter placed in a fluid path between the needle and the cap 615/715 can be used to further regulate the rate of administration of the therapeutic agent, for example, where the plunger actuator 630/730 supplies a spring force without restrictions Thus, an appropriate 630/730 piston actuator and an appropriate flow limiter can be selected to administer the dose at a controlled rate, for example, in a single slow bolus free of or substantially free of any burning sensation to the patient.

In an exemplary embodiment of the present disclosure, pressing the 610/710 therapeutic agent cartridge assembly also damages the retraction mechanism which, when activated, retracts the 610/710 therapeutic agent cartridge assembly into the housing. 635/735.

In step 1020, the therapeutic agent cartridge assembly 610/710 is retracted from the pulsed position to a retracted position in a post-injection state so that it protrudes out of the housing 635/735 and the needle 625/725 retracts inside the 635/735 housing or 660/760 skin sensor foot or both. Figures 6C and 7C illustrate exemplary embodiments of the automatic injection device 600 and 700, respectively, in a retracted position after step 1020. Step 1020 is performed either when the therapeutically effective dose of the therapeutic agent is administered or when the 600/700 portable automatic injection device is removed from the injection site before the therapeutically effective dose is completely administered.

After administration of the therapeutically effective dose, the cap 615/715 and / or the piston actuator 630/730 activates the dose-end retraction activator of the retraction mechanism. The plug 615/715 and / or the piston actuator 630/730 may include a connector member connected to the retraction activator. The connecting member may include a strap or other connection mechanism. The connecting member may be of a suitable length so that, when the cap 615/715 has moved to the end of the 610/710 cartridge assembly (administering a full dose), the connecting member activates a latch which in turn activates the retraction activator.

Once the end of dose retraction activator is activated, the retraction mechanism deploys the therapeutic agent cartridge assembly 610/710 up into the housing 635/735 and away from the patient contact portion so that the 610/710 therapeutic agent cartridge assembly enters a post-injection state. In an exemplary embodiment, the movement of the therapeutic agent cartridge assembly 610/710 from the injection state to the post-injection state creates an audible sound, for example, a "click", which provides an auditory indication of the end of administration of the therapeutic agent. Once retracted, the 610/710 therapeutic agent cartridge assembly protrudes out of the 635/735 housing (as shown in Figures 6C and 7C), which provides a visual indication of the status of the 600/700 portable automatic injection device , for example, end of administration of the therapeutic agent or a visual indication of the device in the post-injection state.

However, if the portable 600/700 device is removed from the patient's skin before the end of the therapeutically effective dose of the therapeutic agent, the 660/760 skin sensing foot extends out of the 635/735 housing and activates the activator of Early withdrawal retraction of the retraction mechanism. Once the early withdrawal retraction activator is activated, the retraction mechanism deploys the therapeutic agent cartridge assembly 610/710 up in the housing 635/735 away from the patient contact portion so that the assembly Therapeutic agent cartridge 610/710 returns to a retracted position. In an exemplary embodiment, the plunger actuator 630/730 can continue to move forward in the therapeutic agent cartridge 610/720 toward the needle 625/725 when the portable device 600/700 is removed from the patient before the end of the administration of a therapeutically effective dose of the therapeutic agent.

In step 1025, after retraction, an automatic needle lock is coupled with the injection needle 625/725 to prevent refolding of the needle 625/725 to provide protection against punctures. The needle lock may be a member that prevents the needle 625/725 from leaving the housing 635/735 once it has been engaged, and can be located in the housing 635/735 near the needle 625/725. Exemplary needle locking may include, but is not limited to, a plastic plate, a metal plate, a clip, etc.

III. Example needle systems

The exemplary embodiments of the present disclosure provide different exemplary needle assemblies for injecting a dose of a therapeutic agent into a patient's skin. In some exemplary embodiments, an injection needle, coupled to a cylinder portion of an exemplary automatic injection device containing the dose, can be inserted into the patient's skin to inject the dose into the skin. of the patient. In other exemplary embodiments, a syringe needle can be attached to a cylinder portion containing the dose to drive the dose out of the cylinder portion, and an injection needle attached to the syringe needle can be inserted into the patient's skin to inject the dose into the patient's skin.

In some exemplary embodiments of the present disclosure, as illustrated in Figures 11 and 12, a syringe may include a cylinder portion and an injection needle coupled to a distal end of the cylinder portion. The injection needle can be inserted into the patient's skin to administer a therapeutic agent contained in the cylinder portion of the syringe. The injection needle can be aligned at any suitable angle with respect to the longitudinal axis of the cylinder portion that varies from about 0 degrees to about 180 degrees.

Figure 11 illustrates an exemplary syringe 1100 suitable for use in an automatic injection device by way of example of the present disclosure. Syringe 1100 includes a cylinder portion 1102 configured to contain a dose of a therapeutic agent and extending between a proximal end and a distal end along a longitudinal L axis. A distal end of the cylinder portion 1102 is coupled to an injection needle 1104 that extends along the longitudinal axis L.

Figure 12 illustrates an exemplary syringe 1200 suitable for use in an exemplary automatic injection device of the present disclosure. Syringe 1200 includes a cylinder portion 1202 configured to contain a dose of a therapeutic agent and extending between a proximal end and a distal end along a longitudinal L axis. A distal end of the cylinder portion 1202 may include an elbow portion 1204 that extends substantially 90 degrees from the longitudinal L axis. A distal end of the elbow portion 1204 is coupled to an injection needle 1206 that extends substantially 90 degrees from the longitudinal L axis. One of ordinary skill in the art will recognize that exemplary automatic injection devices may include injection needles that extend along the longitudinal L axis of the syringe or that extend any suitable angle with respect to the longitudinal L axis of the syringe. syringe. Exemplary angles may include, but are not limited to, approximately 70 degrees to approximately 110 degrees.

In some exemplary embodiments of the present disclosure, as illustrated in Figures 13 and 14, a syringe may include a cylinder portion and an injection needle coupled to a distal end of the cylinder portion. The injection needle can be inserted into a patient's skin to administer a therapeutic agent contained in the cylinder portion of the syringe. The injection needle can be aligned at any suitable angle with respect to the longitudinal axis of the cylinder portion that varies from about 0 degrees to about 180 degrees.

In some exemplary embodiments of the present disclosure, as illustrated in Figures 13 and 14, a syringe may include a cylinder portion and an injection needle directly or indirectly coupled to a distal end of the cylinder portion. The syringe needle can carry a therapeutic agent contained in the cylinder portion of the syringe to the injection needle, and the injection needle can administer the therapeutic agent to the skin of a patient. A coupling between the syringe needle and the injection needle can be provided by one or more intermediate components. An exemplary coupling component may include, for example, an adapter, provided between the distal end of the cylinder portion and the injection needle.

Figure 13 illustrates an exemplary syringe 1300 suitable for use in an automatic injection device by way of example of the present disclosure. Syringe 1300 includes a cylinder portion 1302 configured to extend from a proximal end to a distal end along a longitudinal L axis and configured to contain a dose of a therapeutic agent. A distal end of the cylinder portion 1302 is coupled to a hollow needle syringe 1304. The syringe needle 1304, in turn, is coupled to a hypodermic injection needle 1306 through an exemplary intermediate adapter 1308. More specifically, a proximal portion of the adapter 1308 is coupled to the syringe needle 1304 and a distal portion of the adapter 1308 is coupled to the injection needle 1306. The adapter 1308 can establish an alignment of substantially 90 degrees between the longitudinal axis L of the cylinder portion 1302 and the hypodermic injection needle 1306.

The exemplary adapter 1308 is a component that includes a first portion 1310 extending from the cylinder portion 1302 substantially parallel to the longitudinal axis L, and a second portion 1312 extending from the first portion 1310 substantially perpendicular to the axis L longitudinal. More specifically, a proximal end of the first portion 1310 is coupled to a distal end of the cylinder portion 1302. In an exemplary embodiment, the proximal end of the first portion 1310 may wrap the distal end of the cylinder portion 1302. A distal end of the first portion 1310 is coupled to a proximal end of the second portion 1312. A distal end of the second portion 1312 is coupled to a proximal end of the injection needle 1306. In an exemplary embodiment , the first portion 1310 and the second portion 1312 of the adapter 1308 can be formed entirely.

Exemplary adapters can be formed of a rigid material that includes, but is not limited to, plastic materials, steel, and the like. Exemplary adapters may alternatively be formed of a flexible material that includes, but is not limited to, rubber and the like.

The configuration of the adapter 1308 coupled to the injection needle 1306 allows the injection needle 1306 to extend approximately 90 degrees with respect to the longitudinal axis L of the syringe. This configuration simplifies the manufacture of the portable automatic injection device since it eliminates the need for a bent injection needle. By way of example, the injection needle 1306 maintains a low profile against the patient, while allowing proper insertion into the patient's skin during an injection in an injection state. One of ordinary skill in the art will recognize that exemplary injection needles can be bent from the longitudinal axis of the syringe to any suitable angle not limited to about 90 degrees, for example, about 70 degrees to about 110 degrees.

In some exemplary embodiments of the present disclosure, one or more fluid conduits may be disposed between the syringe needle and the injection needle to allow a flow of the therapeutic agent from the cylinder portion to the injection needle through of the syringe needle. Any suitable fluid conduit or fluid transfer mechanism may be used to establish the one or more fluid conduits between the syringe needle and the injection needle. In an exemplary embodiment of the present disclosure, a perforable partition in its intact state can separate the syringe needle from the fluid communication of the injection needle. When the syringe needle pierces the septum during an injection in an injection state, fluid communication can be established between the syringe needle and the injection needle through the fluid conduit.

Figure 14 illustrates an exemplary portion of an automatic injection device of the present disclosure in which a fluid conduit couples a syringe needle and an injection needle. The device includes a syringe or cartridge assembly having a portion of cylinder 1400 that contains a dose of a therapeutic agent. A distal end of the cylinder portion 1400 is coupled to a syringe needle 1402. A transfer mechanism 1404 is provided in contact with or in the vicinity of the syringe needle 1402, and also in contact with or in the vicinity of a injection needle (not shown). The transfer mechanism 1404 includes a fluid conduit or passage 1406 that establishes fluid communication between the syringe needle 1402 and the injection needle.

In an exemplary embodiment of the present disclosure, the transfer mechanism 1404 includes a pierceable partition 1408 that separates the syringe needle 1402 from the fluid conduit 1406 in the transfer mechanism 1404 before an injection in a pre-injection state . In an exemplary embodiment of the present disclosure, during an injection in an injection state, the syringe or cartridge can be moved towards the transfer mechanism 1404 so that the syringe needle 1402 pierces the partition 1408 to create a trajectory of fluid communication between the cylinder portion 1400, the fluid conduit 1406 of the transfer mechanism 1404 and the injection needle. The therapeutic agent can thus exit the cylinder portion 1400 through the syringe needle 1402 in the fluid conduit 1406. The therapeutic agent can then be transmitted. through fluid conduit 1406 in the injection needle for administration of the therapeutic agent to a patient.

Figure 15 illustrates an exemplary transfer mechanism 1500 for providing a fluid conduit 1502 between a syringe needle (not shown) and an injection needle (not shown). The fluid conduit 1502 may include a centrally extending channel 1504 through which the therapeutic agent circulates from the syringe needle to the injection needle, and raised wall portions 1506 extending along the edges of the channel 1504 to restrict the flow to the channel 1504. The fluid conduit 1502 can take any suitable shape and dimension. In the illustrative embodiment, the fluid conduit 1502 has a substantially straight first portion 1508 aligned approximately 90 degrees from a substantially straight second portion 1510.

The fluid conduit 1502 may include a fluid inlet 1512 for the inlet of the therapeutic agent of the syringe needle, and a fluid outlet 1514 for the outlet of the therapeutic agent in the injection needle. The fluid inlet 1512 can be directly or indirectly coupled to the proximal end of a syringe needle. In an exemplary embodiment, a perforable partition (not shown) can be provided in the fluid inlet 1512 to prevent fluid flow from the syringe needle when the partition is intact, and to allow fluid flow from the syringe needle when the septum is pierced by the syringe needle. The fluid outlet 1514 can be directly or indirectly coupled to the distal end of the injection needle to establish a fluid flow path between the fluid conduit 1502 and the injection needle.

Alternatively, 1512 can be used as the fluid outlet and 1514 can be used as the fluid inlet. In this exemplary embodiment, the fluid inlet 1514 can be directly or indirectly coupled to a syringe needle, and the fluid outlet 1512 can be directly or indirectly coupled to an injection needle.

The transfer mechanism 1500 can be formed from two housing portions 1516 and 1518 stacked together. In an exemplary embodiment, the fluid conduit 1502 can be formed on the surface of the portion 1516, and the portion 1518 can be stacked on the fluid conduit 1502 so as to seal the edges of the fluid conduit 1502 to prevent fluid leakage from the fluid conduit. Compression between the two housing portions 1516 and 1518 can be provided by one or more mechanical interlocking mechanisms, for example, one or more pin screws, pins, chemical bond, ultrasonic welding, and others.

The fluid conduit 1502 can be formed on the surface of the housing portion 1516 using any suitable technology. In an exemplary embodiment, the raised wall portions 1506 of the fluid conduit 1502 may be formed of a molded low durometer material such as a bushing to seal the flow path of the therapeutic agent. In another exemplary embodiment, laser welding can be used to trace a path around the perimeter of channel 1504 to simultaneously create a joint around channel 1504 and join together the two housing portions 1516 and 1518.

Figure 16 illustrates an exemplary transfer mechanism 1600 for providing a fluid conduit 1602 between a syringe with a syringe needle 1604 coupled to a cylinder portion 1606 and an injection needle (not shown). The transfer mechanism 1600 may include a first portion 1608 having a partition 1610 provided in the vicinity of the syringe needle 1604.

The first portion 1608 of the transfer mechanism 1600 may include a hollow internal space to accommodate the therapeutic agent and an inlet port 1612 coupled to one end of a hollow tube 1614. The other end of the hollow tube 1614 is coupled directly or indirectly (by example, through a second portion similar to the first portion 1608) to the injection needle. The hollow tube 1614 provides a fluid path from the syringe needle 1604 to the injection needle. The hollow tube 1614 can take any suitable shape, alignment and dimension. In the illustrative embodiment, the hollow tube 1614 extends substantially at right angles to the longitudinal axis of the cylinder portion 1606.

In an exemplary embodiment of the present disclosure, the transfer mechanism 1600 may be movable up and / or down along the vertical axis. In this embodiment, prior to an injection in a pre-injection state (for example, when the syringe needle is covered by a needle cover), the transfer mechanism 1600 may be in a vertically raised position above the syringe needle 1604 so that the syringe needle 1604 is not aligned with the partition 1610 in the transfer mechanism 1600, thus preventing fluid communication between the syringe needle 1604 and the transfer mechanism 1600. At the beginning of an injection (for example, after With removal of the syringe needle syringe cap 1604), the transfer mechanism 1600 can be automatically lowered to a vertically lowered position so that the syringe needle 1604 aligns with the partition 1610 in the transfer mechanism 1600 , thus allowing syringe needle 1604 to pierce septum 1610. Exemplary embodiments can provide any actuation mechanism suitable for b move the transfer mechanism 1600 from the vertically raised position to the vertically lowered position at the beginning of an injection.

In an exemplary embodiment of the present disclosure, syringe needle 1604 may initially be coupled to or provided immediately adjacent to the first portion 1608. In another embodiment of the present disclosure, the syringe may be in a retraction position within the portable automatic injection device and syringe needle 1604 may initially be separated from the first portion 1608 of the transfer mechanism 1600. In this embodiment of the present disclosure, prior to an injection in a pre-injection state, the syringe needle 1604 may be separated from the partition 1610 in the first portion 1608 and may not be in fluid communication with the transfer mechanism 1600. At the beginning of an injection, the syringe can be moved forward by a cartridge or syringe activator to an extended position within the device, and the syringe needle 1604 can pierce the partition 1610, allowing the therapeutic agent circulates from the cylinder portion 1606 to the transfer mechanism 1600. The Exemplary embodiments of the present disclosure may provide any syringe or cartridge activation mechanism suitable for advancing the cylinder portion and / or the cartridge assembly within the housing between the retracted position and the extended position for perforating the septum. and transporting the therapeutic agent to the patient's skin through the injection needle.

An advantage of the exemplary transfer mechanism 1600 is that the movements of the syringe needle 1604 and the injection needle are disengaged and independent of each other. For example, the mechanism that couples the syringe needle 1604 to the inlet port 1612 does not need to take into account how this coupling would affect the output of the transfer mechanism 1600 coupled to the injection needle.

Figure 17 illustrates an exemplary transfer mechanism 1700 for providing a fluid conduit between a syringe having a syringe needle 1704 coupled to a cylinder portion 1706 and an injection needle (not shown). The transfer mechanism 1700 may include an inlet portion (not shown) attachable to syringe needle 1704 and an outlet portion (not shown) attachable to the injection needle. A hollow tube 1708, for example, a bridge tube, can be used to couple the inlet portion of the transfer mechanism to the outlet portion of the transfer mechanism. The hollow tube 1708 provides a fluid path from the syringe needle 1704 to the injection needle. The hollow tube 1708 can take any suitable shape, alignment and dimension. In the illustrative embodiment, the hollow tube 1708 extends substantially at right angles to the longitudinal axis of the cylinder portion 1706.

In an exemplary embodiment of the present disclosure, the inlet portion of the transfer mechanism 1700 may include a partition (not shown) provided in the vicinity of the syringe needle 1704. The perforation of the partition by the syringe needle 1704 it can establish fluid communication between the cylinder portion 1706 and the transfer mechanism 1700. In an exemplary embodiment of the present disclosure, the output portion of the transfer mechanism may include a partition (not shown) provided in the vicinity of the injection needle. Perforation of the septum by the injection needle can establish fluid communication between the transfer mechanism 1700 and the patient's skin.

In an exemplary embodiment of the present disclosure, the transfer mechanism 1700 can be movable up and / or down along the vertical axis. In this embodiment of the present disclosure, prior to an injection in a pre-injection state (for example, when the syringe needle is covered by a needle cover), the transfer mechanism 1700 may be in a vertically raised position above the syringe needle 1704 so that syringe needle 1704 is not aligned with the partition in the transfer mechanism 1700, thus preventing fluid communication between the syringe needle 1704 and the transfer mechanism 1700. At the beginning of an injection (by For example, after removal of the syringe needle syringe cap 1704), the transfer mechanism 1700 can be automatically lowered to a vertically lowered position so that the syringe needle 1704 aligns with the septum in the mechanism of transfer 1700, thus allowing syringe needle 1704 to pierce the septum. Exemplary embodiments may provide any activation mechanism suitable for lowering the transfer mechanism 1700 from the vertically raised position to the vertically lowered position at the beginning of an injection.

In an exemplary embodiment of the present disclosure, the syringe needle 1704 may be initially coupled to or provided immediately adjacent to the first portion 1708. In another embodiment of the present disclosure, the syringe may be in a retraction position within of the portable automatic injection device and the syringe needle 1704 may initially be separated from the transfer mechanism 1700. In this embodiment of the present disclosure, prior to an injection in a pre-injection state, the syringe needle 1704 may be separated from the partition and may not be in fluid communication with the transfer mechanism 1700. At the beginning of an injection, the syringe can be moved forward by a cartridge or syringe activator to an extended position within the device, and syringe needle 1704 it can pierce the septum, allowing the therapeutic agent to circulate from the cylinder portion or 1706 to transfer mechanism 1700. Exemplary embodiments of the present disclosure may provide any suitable syringe or cartridge activation mechanism for advancing the cylinder portion and / or cartridge assembly within the housing between the retracted position and extended position to pierce the septum and transport the therapeutic agent to the patient's skin through the injection needle.

In the exemplary embodiments of the present disclosure illustrated in 15-17, a fluid path Tightly and reliably transports the therapeutic agent from the cylinder portion of a syringe or cartridge through a perforated septum and a tube or channel in a transfer mechanism and possibly in an injection needle. This configuration allows the syringe needle assembly and the injection needle assembly to move independently of each other, which facilitates retraction of the injection needle into the housing in a post-injection state after performing an injection, while which leaves the syringe needle in a position where it pierces the septum.

Figures 18A and 18B illustrate an exemplary portable automatic injection device of the present disclosure that includes a syringe and an exemplary transfer mechanism. Figure 18A illustrates a perspective view of the device. Figure 18B illustrates a disassembled view showing the components of the device. Automatic injection device 1800 includes a housing portion 1802 that includes a layer of adhesive 1804 in a region of contact with the patient that can be removed to attach the device to a patient's body or clothing.

The housing portion 1802 contains a syringe 1806 in a stationary or mobile mode in the device 1800. The syringe 1806 contains a dose of a therapeutic agent and that is coupled to a syringe needle 1808 at its distal end. Syringe needle 1808 can be extended substantially along the longitudinal axis of syringe 1806. In a pre-injection packaged state, syringe needle 1808 can be covered by a needle cover of syringe 1805, which can be removed by a patient before an injection. In an injection state, syringe needle 1808 may be uncovered. In an exemplary embodiment, the removal of the adhesive layer 1804 can also remove the needle cover of the syringe 1805.

An injection button 1810 is provided in the vicinity of syringe needle 1808. The injection button 1810 includes contains an injection needle 1812 at substantially 90 degrees with respect to syringe needle 1808, and includes a transfer mechanism that provides a fluid conduit between syringe needle 1808 and injection needle 1812. In a packaged pre-injection state, injection needle 1812 can be covered by an injection needle cap 1813, which can be removed by a patient before an injection. In an injection state, the injection needle 1812 may be uncovered. In an exemplary embodiment, removal of the adhesive layer 1804 can also remove the injection needle cover 1813.

The injection button 1810 also includes a partition 1811 that prevents syringe needle 1808 from establishing fluid communication with the fluid conduit in the injection button 1810. A cap 1813 can be provided to cover the partition 1811 in a pre-injection state. , which can be removed by a patient before an injection. In an exemplary embodiment, the septum cover 1813 and the needle cover of the syringe 1805 can be coupled so that removal of one also removes the other.

In an exemplary embodiment of the present disclosure, in a pre- and post-injection state, the needle cover of the syringe 1805 may cover the syringe needle 1808, and the injection button 1810 may be in a position vertically raised to as it travels through the needle cover of the syringe 1805 so that the injection needle 1812 retracts into the housing 1802. In this state, the partition 1811 of the injection button 1810 can be vertically above the syringe needle 1808 In addition, the syringe 1806 may be in a retracted position along the longitudinal axis of the assembly 1806 separated from the partition 1811 of the injection button 1810.

When the needle cover of the syringe 1805 is removed from the syringe needle 1808, the injection button 1810 drops to a vertically lowered position so that the injection needle 1812 protrudes out of the housing 1802 into the patient contact region . In an exemplary embodiment, the injection button 1810 can be automatically lowered by the withdrawal of the needle cover of the syringe 1805. In another exemplary embodiment, the injection button 1810 is lowered by the patient by pushing down on the 1810 injection button.

In an exemplary embodiment of the present disclosure, the lowering of the injection button 1810 aligns the syringe needle 1808 with the partition 1811 of the injection button 1810. The lowering of the injection button 1810 also activates a syringe activator that advance the syringe 1806 along its longitudinal axis toward the partition 1811 of the injection button 1810. This causes the syringe needle 1808 to pierce the partition 1811 and establish fluid communication with the injection needle 1812.

Figures 19A and 19B illustrate an exemplary portable automatic injection device of the present disclosure that includes a syringe and an exemplary transfer mechanism. Figure 19A illustrates a side view of the device. Figure 19B illustrates a perspective view showing the components of the device. The automatic injection device 1900 includes a housing 1902 containing a syringe 1904 in a stationary or mobile mode with respect to the housing 1902. An injection button 1906 is provided in the housing 1902 in the vicinity of the syringe 1904 and supports a needle injection (not shown). Housing 1902 includes a layer of adhesive 1908 for bonding in a region of contact with the patient.

Other components in device 1900 similar to components in device 1800 are described with reference to Figures 18A and 18B.

Figures 20A-20C illustrate an exemplary portable automatic injection device of the present disclosure that includes an example cartridge assembly and transfer mechanism. Figure 20A illustrates a perspective view of the device. Figure 20B illustrates a top view of the device. Figure 20C illustrates a side view of the device transfer mechanism. The automatic injection device 2000 includes a housing 2002 having a layer of adhesive 2003 for bonding in a region of contact with the patient. The housing 2002 contains a cartridge 2004 in a stationary or mobile mode with respect to the housing 2002. The cartridge 2004 is configured to contain a dose of a therapeutic agent. An injection button 2006 is provided in the housing 2002 in the vicinity of the cartridge 2004. The injection button 2006 may support or be coupled to an injection needle 2008 that extends substantially 90 degrees with respect to the longitudinal axis of the cartridge 2004 and a 2010 syringe needle extending substantially parallel to the longitudinal axis of the cartridge 2004. The injection button 2006 may form or include a transfer mechanism that establishes fluid communication between the cartridge 2004 and the injection needle 2008 through the syringe needle 2010

The injection button 2006 may include a housing coupling portion 2012 that engages with a housing portion 2014 when the injection button 2006 is pressed during an injection in an injection state. In an exemplary embodiment illustrated in Figure 20C, the coupling between the housing coupling portion 2012 and the housing portion 2014 causes the housing portion 2014 to move parallel to the longitudinal axis of the cartridge 2004 toward the distal end of the cartridge 2004, thus allowing the syringe needle 2010 to establish fluid communication with the cylinder portion of the cartridge 2004. In another exemplary embodiment, the coupling between the housing coupling portion 2012 and the housing portion 2014 causes the 2004 cartridge moves parallel to the longitudinal axis of the 2004 cartridge towards the syringe needle 2010, thus allowing the 2010 syringe needle to establish fluid communication with the cylinder portion of the 2004 cartridge.

Other components in device 2000 similar to the components in device 1800 are described with reference to Figures 18A and 18B.

Figures 21A-21C illustrate an exemplary portable automatic injection device of the present disclosure that includes an exemplary cartridge assembly. Figure 21A illustrates a perspective view of the automatic portable injection device by way of example. Figure 21B illustrates a sectional view of the cartridge assembly along a longitudinal axis. Figure 21C illustrates a transparent top view of the device transfer mechanism. The automatic injection device 2100 includes a housing 2102 having an adhesive layer 2103 for bonding in a region of contact with the patient. The housing 2102 contains a cartridge 2104 in a stationary or mobile mode with respect to the housing 2102. The cartridge 2104 is configured to contain a dose of a therapeutic agent. A proximal end of cartridge 2104 includes a cap 2106 and a distal end of cartridge 2104 includes a partition 2108 that jointly seals the dose within cartridge 2104.

An injection button 2110 is provided in the housing 2102 in the vicinity of the cartridge 2104. The injection button 2110 contains an injection needle at a proximal end that extends substantially 90 degrees with respect to the longitudinal axis of the cartridge 2104. The Injection 2110 is coupled to a transfer mechanism 2111 containing a syringe needle 2112 in the vicinity of the cartridge 2104. The syringe needle 2112 extends substantially parallel to the longitudinal axis of the cartridge 2104. The transfer mechanism 2111 includes a fluid conduit to establish fluid communication between the cartridge 2104 and the injection needle 2108 through the syringe needle 2110. In a pre-injection state, the syringe needle 2112 may be partially extended at a distal end of the cartridge 2104, but may be separated from the partition 2108. In an injection state, the plug 2106 can be moved inside the cartridge 2104 so that the pressure of the fluid in the cartridge 2104 move the partition 2108 forward towards the syringe needle 2112. This causes the syringe needle 2112 to pierce the partition 2108 and establish fluid communication between the cartridge 2104 and the injection needle through the needle syringe 2112.

Other components in device 2100 similar to components in device 1800 are described with reference to Figures 18A and 18B.

Figure 22 illustrates an exemplary syringe or cartridge actuator 2200 that can be used to advance a syringe 2202 or a cartridge assembly from a retraction position to an extended position within the housing of an automatic portable injection device. of the present disclosure. A proximal end of the cylinder portion and / or the cartridge assembly can be coupled to a deflection member 2204, for example, a drive spring, which applies a force on the cylinder portion of the syringe assembly and / or cartridge to move the cylinder portion and / or the cartridge assembly toward a partition in a transfer mechanism (not shown). The syringe or cartridge actuator 2200 may be contrary to the deflection force of the deflection member, and may support and block the cylinder portion and / or the cartridge assembly in a retracted position in a stable and reliable mode.

When activated, the syringe or cartridge actuator 2200 may allow the cylinder portion and / or the cartridge assembly to move forward towards the partition under the force of the deflection member. In an exemplary embodiment, the syringe or cartridge actuator 2200 can be configured and / or set at a certain distance to control the level of the activation force required to advance the cylinder portion and / or the cartridge assembly from the retracted position to the extended position.

Any suitable activating mechanism can be used to activate the activation mechanisms of the syringe or cartridge. In an exemplary embodiment, the activating mechanism can automatically activate the syringe or cartridge activation system when the portable automatic injection device moves from a pre-injection state to an injection state. In an exemplary embodiment, the downward vertical movement of an injection button within the housing to provide a fluid path between the syringe or cartridge assembly and the injection needle can provide an activating force to activate the injection system. piston activation. In another exemplary embodiment, forward movement of the syringe or cartridge assembly into the housing to establish a fluid path between the syringe or cartridge assembly and the injection needle can provide an activating force to activate the syringe or cartridge system. In another exemplary embodiment, the syringe or cartridge system can be manually activated by a user.

Prior to an injection in a pre-injection state, a needle cover, for example, a soft and rigid needle cap assembly (not shown), provided at the distal end of the syringe can protectively cover the syringe needle. At this stage, since the syringe needle is covered with the needle cover, the distal end of the syringe has a first larger diameter. As such, the transfer mechanism that includes the septum is maintained in a vertically raised position above the needle cover, and the septum is not aligned with the syringe needle. When the needle cover is removed from the syringe in preparation for an injection (for example, manually by a user or by an automatic mechanism), the transfer mechanism is allowed to fall to a vertically lowered position since it is no longer kept displaced by the rigid needle cap, and the partition in the transfer mechanism is aligned with the syringe needle. The withdrawal of the needle cover thus lowers the transfer mechanism from its raised position to its lowered position. The lowering of the transfer mechanism, in turn, applies an activating force to the syringe or cartridge actuator 2200 and operates as the activating mechanism for the syringe or cartridge actuator 2200.

Figure 23 illustrates an exemplary syringe or cartridge actuator 2300 that includes a first portion 2302, a second portion 2304 and a hinge portion 2306 provided between the first and second portions. Hinge portion 2306 allows the first and second portions to rotate around the hinge with respect to each other. In different rotational configurations, the first and second portions may have exemplary angles of between about 0 degrees and about 180 degrees to each other. The activator 2300 can be coupled to the syringe and the partition and / or the transfer mechanism. When the partition and / or transfer mechanism is in its first raised position, the activator 2300 can hold the syringe in place in its retracted position. When the partition and / or transfer mechanism is in its second lowered position, the activator 2300 can release the syringe so that the deflection member can push the syringe forward to its extended position to pierce the partition.

IV. Piston drive systems and needle retraction systems by way of example

The exemplary embodiments of the present disclosure provide plunger activation systems for actuating a plug in a cylinder portion of an automatic portable injection device so that the plug moves forward within the cylinder portion and expels a dose of a therapeutic agent contained in the cylinder portion. Any suitable activating mechanism can be used to activate the piston drive systems. In an exemplary embodiment, the activating mechanism can automatically activate the plunger drive system when the portable automatic injection device moves from a pre-injection state to an injection state. In an exemplary embodiment, the downward vertical movement of an injection button within the housing to provide a fluid path between the syringe or cartridge assembly and the injection needle can provide an activating force to activate the injection system. piston drive In another exemplary embodiment, forward movement of the syringe or cartridge assembly into the housing to establish a fluid path between the syringe or cartridge assembly and the injection needle can provide an activating force to activate the piston drive system. In another exemplary embodiment, the piston drive system can be manually activated by a user.

Certain other exemplary embodiments of the present disclosure provide plunger devices and drive systems that cause the plunger of the syringe to run at a slow speed to deliver the therapeutic agent to a patient at a slow speed. Slow exemplary embodiments may administer therapeutic agent volumes of about 0.1 milliliters to about 1 milliliter or more in about five minutes to about thirty minutes, although the rates of Administration by way of example is not limited to this interval by way of example.

The exemplary embodiments of the present disclosure may provide a linear administration profile for the therapeutic agent so that the rate of administration is substantially constant over time. In some cases, a linear administration profile may reduce the discomfort experienced by the patient.

Figure 24 illustrates a schematic of a portion of an exemplary automatic injection device of the present disclosure 2400 that includes a plunger drive mechanism employing a snail and a viscous damping mechanism. The portable automatic injection device 240 ° includes a housing 2402 having a platform 2410 which is a mechanical structure to support a syringe or cartridge assembly 2404 in place within the portable automatic injection device 2400. The syringe or cartridge 2404 includes a cylinder portion to support a dose of a therapeutic agent and a plug 2408 to seal the dose within the cylinder portion. A piston drive mechanism 2406 is provided to move the plug 2408 into the cylinder portion to expel the dose from the cylinder portion. A damping mechanism 2422, for example, a viscous buffer, is provided to regulate the movement of the plug 2408 so that the therapeutic agent is administered in a linear manner, that is, at a substantially constant flow rate. A gear train 2420 may be provided that includes one or more gears to couple the plunger drive mechanism 2406 to the damping mechanism 2422. The gear train 2420 may include any number of suitable gears to provide any suitable transmission ratio.

The platform 2410 of the automatic portable injection device 2400 can be stationary or mobile. In an exemplary embodiment, the platform 2410 may be a substantially box-shaped or cylindrical structure with an internal space to accommodate the syringe or cartridge 2404. The peripheral walls surrounding the internal space can be configured to support an assembly of syringe or cartridge 2404 in place. The platform 2410 may include one or more clamping mechanisms 2412 to support the syringe or cartridge 2404 in place. The platform 2410 may also include a flange bearing 2414 provided at the proximal end of the syringe or cartridge 2404. A flange provided at the proximal end of the syringe or cartridge 2404 can slide back against the flange bearing 2414.

In an exemplary embodiment of the present disclosure, the platform 2410 can support the syringe or cartridge 2404 stationary within and with respect to the platform 2410. In another exemplary embodiment of the present disclosure, the platform 2410 it can allow the syringe or cartridge 2404 to move with respect to the platform 2410, for example, towards or away from a fluid transfer mechanism (not shown). In this exemplary embodiment, the internal space of the platform 2410 may include one or more slots, rails or channels to facilitate the movement of the syringe or cartridge 2404 within the platform 2410. In an exemplary embodiment, the platform 2410 may include a window 2416, for example, a cut or a transparent portion, to allow the patient to see the syringe or cartridge 2404.

One or more plunger actuators 2406 may be provided in the vicinity of the syringe or cartridge 2404 to store the energy and provide a force to drive a plug 2408 inside the syringe or cartridge 2404 towards the distal end of the syringe or cartridge 2404. In an exemplary embodiment of the present disclosure, a piston actuator 2406, for example, a helical compression spring, can be used to drive the plug 2408. The piston actuator 2406 can be provided at least partially within the syringe or cartridge 2404. Before an injection in a pre-injection state, the plunger actuator 2406 can be kept in a compressed state. At the beginning of an injection or during an injection in an injection state, the plunger actuator 2406 can be allowed to expand from the compressed state to a released state. Expansion of the plunger actuator 2406 can push the cap 2408 toward the distal end of the syringe or cartridge 2404, thereby expelling the therapeutic agent from the syringe or cartridge 2404. Advantageously, the configuration of the plunger actuator 2406 into the syringe or cartridge 2404 does not add to the length of the housing required to support the syringe or cartridge 2404. However, in some exemplary embodiments, the plunger actuator 2406 may not provide a constant force to drive the plug 2408.

In another exemplary embodiment of the present disclosure, a spiral spring may be used to drive the plug 2408. The spiral spring may be provided outside but along the syringe or cartridge 2404 within the platform 2410, which can add to the space requirement of the housing 2402. Before an injection in a pre-injection state, the spring can be kept in a compressed state. At the beginning of an injection or during an injection in an injection state, the spring can be allowed to expand from the compressed state to a released state. The expansion of the spring can push the cap 2408 towards the distal end of the syringe or cartridge 2404, thereby expelling the therapeutic agent from the syringe or cartridge 2404. Advantageously, the spiral spring can provide a substantially constant force to drive the cap 2408.

One or more damping mechanisms may be provided to regulate the release of energy in the plunger actuator 2406 to control the rate of administration and / or the time of administration to administer the therapeutic agent. In an exemplary embodiment, in order to achieve a slow and / or controlled release, the piston actuator 2406 is prevented from accelerating without resistance from its compressed state. Until a state released. The movement of the piston actuator 2406 can be maintained at a constant speed, for example, by providing linear damping values. Any suitable mechanism can be used to provide resistance against acceleration of the plunger actuator 2406. In an exemplary embodiment, a rotating viscous damper 2422 can be used to resist acceleration of the piston actuator 2406. The viscous damper 2422 can use one or more viscous fluids, for example, silicon grease, to provide resistance. The viscous damper 2422 may include a stationary housing containing a solid rotating element called a "rotor." The outer circumference of the rotor may include a plurality of teeth configured to be coupled by the teeth of a gear in the gear train 2420. The rotor may be surrounded by a thin film of a viscous fluid that is sealed within the housing. Rotation of the rotor can provide resistance against acceleration of the piston actuator 2406 by shearing the viscous fluid. In an exemplary embodiment, viscous buffer 2422 can be replaced with a different viscous buffer that provides a different level of damping.

The force required to rotate the viscous rotary damper 2422 is described with reference to a coordinate system x where x = 0 is in the free length of a spring. If m is the inertia of the system, c is the damping coefficient, and k is the spring constant, then:

where the natural frequency:

and where the damping ratio:

If the damping is driven by a rotating damper, it can be assumed that the torque required to rotate the damper is linearly proportional to the angular velocity by a certain constant C:

If the rotary damper is coupled to the piston actuator by a reduction gear train N and a coil of diameter D, then:

In another exemplary embodiment of the present disclosure, an exhaust can be used to resist acceleration of the plunger actuator 2406. The exhaust can use a known oscillation period of a balance wheel and a spiral clock spring to release gradually the energy of a main spring. An escape can provide unreliable design and linearity in the release of energy. In another embodiment by way of For example, an out-of-control exhaust can be used to resist acceleration of the piston actuator 2406. In another exemplary embodiment, a Swiss anchor escape can be used to resist acceleration of the piston actuator 2406.

A gear train 2420 can be provided to couple the plunger actuator 2406 to the regulator device 2422, that is, the viscous damper or the exhaust. The gear train 2420 may include a rod 2424 that can be attached to the housing 2402 of the portable automatic injection device 2400 with a fine sliding adjustment. In an exemplary embodiment, the rod 2424 can support a cylindrical structure 2426, for example, a coil or a rod, and a gear 2428 that is provided below the coil 2426. In an exemplary embodiment, the coil 2426 can be a cam coil or a snail. One or more elastic rings 2430 can be used to retain the coil 2426 and the gear 2428 on the rod 2424. The coil 2426 and the gear 2428 can be provided around the rod 2424 so that the centers of rotation of the coil 2426 and the gear 2428 align with each other and with the rod 2424. The coil 2426 and the gear 2428 can be coupled together with each other and the rod 2424 so that the gear 2428 and the coil 2426 can rotate together on the rod 2424. In one embodiment by way of example, coil 2426 and gear 2428 can be removed from rod 2424 and replaced with a different set of coils and gears. Piston actuator 2406 can be coupled to the gear train, for example, coil 2426, using one or more belts or cables 2442.

In an exemplary embodiment of the present disclosure, coil 2426 may be any suitable rotation mechanism that includes, but is not limited to, a constant diameter coil, a cam or snail coil. If a cam or snail is used, the external diameter of the cam or snail can vary with the linear displacement D. Taking the equation for the linear damping coefficient and supporting the reduction of gears N and the constant rotating damping coefficient gives:

Where a is constant. Substituting the above in the equation of motion and assuming that the first derivative of x is constant, gives:

^{where Ci, C} 2 ^{and b are constants that can be varied to make the velocity approximately constant.} By entering this variable in the equation of motion and solving for x as a function of time, x can be substituted in equation (8) to determine D as a function of time, Dt. The instantaneous velocity can be represented as:

where ^ is the angular position of the cam or snail. D ^t and are the polar coordinates of the cam profile.

The exemplary embodiments of the present disclosure can couple the plunger actuator 2406 to a stopper in the cylinder portion of a syringe or cartridge using any suitable mechanism. If a compression spring is used as the piston actuator 2406, one or more belts or cables can be used to attach the piston actuator 2406 to the plug. If a spiral spring is used as the plunger actuator 2406, straight tooth gear can be used to attach the plunger actuator 2406 to the plug. The torque generated by the spiral spring can be attached to the cap using a pinion to push a flexible frame around the corner of the syringe or cartridge.

In an exemplary embodiment of the present disclosure, the coil 2426 may be in contact with and / or coupled to a sprocket 2434 and ratchet 2436. A torsion spring (not shown) may be provided under the ratchet 2436 to preload the ratchet 2436 against the sprocket 2434. When the coil 2426 is being rolled during the assembly of the portable automatic injection device 2400, the torsion spring can be held in place. After the coil 2426 has been wound and before an injection in a pre-injection state, the cogwheel 2434 and the ratchet 2436 can support the coil 2426 in place and prevent the rotational movement of the coil 2426. This supports the belt 2442 in place which, in turn, keeps the plunger actuator 2406 in its compressed state, preventing the movement of the plunger. At the beginning of a injection or during an injection in an injection state, the ratchet 2436 can be rotated to disengage the sprocket 2434, for example, by a user or automatically after pressing an injection button. This allows the coil 2426 to rotate under the tensile force of the belt 2442 caused by the force of the spring of the plunger actuator 2406. The force of the spring of the plunger actuator 2406 pulls the belt 2442 towards the distal end of the syringe or cartridge 2404.

One or more additional gears can be provided in contact with and / or coupled to the gear coupled to the coil 2426, thus forming a gear train 2438. Each gear in the gear train 2438 can be provided in a corresponding rod coupled to the housing. 2402 of the automatic portable injection device 2400. In an exemplary embodiment, the gears in the gear train 2438 can be removed from their corresponding stems and repositioned with a different set of gears. A person skilled in the art will recognize that other exemplary devices may include less or more gears. The gear train 2438 can be coupled to the viscous shock absorber 2422 or an exhaust that resists the acceleration of the plug 2408. That is, the gear train can attach the viscous shock absorber 2422 or an escape to the belt 2442 containing the plug 2408 so that, when the plug 2408 moves under the force of the piston actuator 2406, the acceleration of the piston actuator 2406 is resisted by the viscous damper 2422 or the exhaust.

In an exemplary embodiment of the present disclosure, the gear train 2438 can be coupled to a coding device 2440, for example, a rotary encoder, which detects and records the angular displacement or position of the gear train and the time correspondent. A computing device can be associated with the portable automatic injection device to determine the position of the syringe plunger based on the data obtained by the encoder device 2440. The computing device can also determine the flow rate of the therapeutic agent of the syringe or cartridge 2404 and the corresponding time based on the data obtained by the encoder device 2440. The computing device can be provided entirely with the encoder device 2440 or separately from the encoder device 2440. During the assembly and testing of the automatic portable injection device, The encoder device 2440 can be used to evaluate different gear trains, viscous dampers and deflection elements, validate mathematical models and explain untreated variables in mathematical models. During the use of the portable automatic injection device to perform an injection, the encoder device 2440 can be used to indicate one or more conditions to the user, for example, the flow rate of the therapeutic agent, the device malfunctioning (e.g., if the flow it is too high or too low), and the like.

In an exemplary embodiment of the present disclosure illustrated in Figures 25 and 26, an automatic portable injection device may include a mobile syringe assembly with respect to a platform in the device. The portable automatic injection device includes a platform 2500, a slide car 2502 coupled to the platform 2500 and a syringe 2504 mounted on the slide car 2502. A distal end of the syringe 2504 can be coupled to a syringe needle 2512. The syringe 2504 may include a cylinder portion 2506 containing a dose of a therapeutic agent sealed by a cap 2508. A piston actuator 2510 may be provided in the vicinity or in contact with the cap 2508 to move the cap 2508 forward into the cylinder portion 2506. In an exemplary embodiment, the piston actuator 2510 may include a deflection mechanism coupled by a belt to a gear train and thus to a damping mechanism.

The device may also include an injection button that carries an injection needle (not shown) and that includes a pierceable septum that can be pierced by syringe needle 2512. The septum can be attached directly or through a conduit to the needle. of injection so that, when pierced by syringe needle 2512, the partition establishes fluid communication between the cylinder portion 2506 and the injection needle. In an exemplary embodiment of the present disclosure, in a pre-injection state, syringe needle 2512 may already pierce the septum and be in fluid communication with the injection needle.

During an injection in an injection state, the dose of the therapeutic agent can be expelled from the cylinder portion 2506 when the piston actuator 2510 is activated to move the plug 2508 forward into the cylinder portion 2506. In this embodiment, carriage 2502 may be stationary on platform 2500. In another exemplary embodiment, in a pre-injection state, syringe needle 2512 may be separated from the partition and may not be in fluid communication with the injection needle. During an injection in an injection state, the syringe 2504 can be moved forward within and with respect to the platform 2500 towards the partition to pierce the partition with the syringe needle 2512. In this exemplary embodiment, the carriage 2502 can be mobile and can move with respect to platform 2500 towards the partition.

In an exemplary embodiment, a belt 2516 can be used to couple the plunger actuator 2510 to a gear train 2518. The gear train 2518 can in turn be coupled to a damping mechanism 2520 to provide a profile of linear administration of the therapeutic agent. In a pre state Injection, a locking mechanism 2522 can support the gear train 2518 in place and prevent the rotation of the gears. This causes the belt 2516 to support the piston actuator 2510 in place and prevent the release of the piston actuator 2510, thus preventing the movement of the plug 2508. During an injection in an injection state, the closing mechanism 2522 can be released , for example, manually by a user or automatically, thus allowing gears 2518 to rotate under the deflection force of piston actuator 2510. This may allow mobile carriage 2502 to automatically move towards the partition, which results in the 2512 syringe needle pierces the septum. The cap 2508 can also be moved within the cylinder portion 2506 towards the partition under the deflection force of the plunger actuator 2510 to expel the dose through the syringe needle 2512.

Figures 27-29 illustrate a schematic of a portion of an exemplary automatic injection device that may include a syringe assembly that is stationary with respect to the device housing. The portable automatic injection device 2800 includes a piston drive mechanism for automatically actuating a plug 2802 in a cylinder portion 2804. Figure 27 is a top view through a cover of the device 2800. Figure 28 is a view side of device 2800. Figure 29 is a perspective view through a cover of device 2800.

The plunger drive mechanism may include a deflection mechanism 2806 that operates as the plunger actuator. In an exemplary embodiment, one or more belts or cables 2812 can be used to couple the deflection mechanism 2806 to a 3-stage gear 2810, for example a snail, which is unwound to allow the deflection mechanism to expand 2806. A 1-stage shock absorber 2808, for example, a viscous damper or an exhaust, regulates the movement of the plug 2802 during an injection in an injection state to achieve a linear flow rate of the therapeutic agent. One or more 2-stage gears and pinions 2814 can be used to couple the 3-stage gear 2810 and the 1-stage damper 2808.

Table 7 summarizes exemplary features of an exemplary 1-stage damper, an exemplary 2-stage gear, an exemplary 2-stage pinion and an exemplary 3-stage gear that they can be used in automatic injection devices as an example.

Table 7: Example features of piston drive components by way of em

Failure analysis was performed on the plunger drive mechanism as an example. In an exemplary embodiment, the gear train (including 2-stage gear) is designed assuming a Lewis bending failure mode that assumes that the gear tooth is a simple beam with contact of teeth that occur in the tip. The results of the fault analysis summarized in Table 7 indicate that the minimum safety factor for the gear train is 3 and that the total gear ratio is 4.04.

Different combinations of different types of piston actuators (spring 1 and spring 2), coils (constant diameter coil or cam coil) and damping mechanisms (viscous or exhaust damper) were tested to determine their effect on the speed of administration of the therapeutic agent Figure 30 illustrates the x and y coordinates (in inches) of cam profiles for: (i) the combination of spring 1 and a viscous damper, (ii) the combination of spring 1 and an exhaust, (iii) the combination of spring 2 and a viscous damper, and (iv) the combination of spring 2 and an exhaust.

Figure 31 illustrates a graph of therapeutic agent flow rates (in milliliters per minute) versus time (in seconds) administered by: (i) the combination of spring 1 and a viscous buffer, (ii) the combination of spring 1, a viscous damper and a cam coil, (iii) the combination of spring 1 and an exhaust, (iv) the combination of spring 1, an exhaust and a cam coil, (v) the combination of spring 2 and a viscous damper, (vi) the combination of spring 2, a viscous damper and a cam coil, (vii) the combination of spring 2 and an exhaust, (viii) the combination of spring 2, an exhaust and a cam coil, and (ix ) and an ideal flow rate in which the therapeutic agent is administered at a substantially constant rate. Figure 32 illustrates a graph of the therapeutic agent volume (in milliliters) versus time (in seconds) administered by the combinations of the components of Figure 31.

Figures 31 and 32 show that a substantially linear flow rate of the therapeutic agent can be achieved using a cam coil or a snail. The use of an exhaust, versus a viscous damper, can be used to improve the linearity of the flow. The total administration time of the therapeutic agent can be controlled by setting the gear ratio.

Different example damper combinations and exemplary gear ratios were tested on exemplary piston drive mechanisms. Exemplary dampers included: (i) damping mechanism G, (ii) damping mechanism B, (iii) damping mechanism K and (iv) damping mechanism V. Example gear ratios included: (i) 4: 1, (ii) 6.25: 1, and (iii) 16: 1. Figure 33 illustrates a graph of the volume of therapeutic agent (in milliliters) versus time (in seconds) administered using: (i) a damping mechanism G having a damping coefficient of approximately 10.3 lbf * s / in ( 18,025 N s / cm) with a gear ratio of 4: 1, (ii) a damping mechanism B that has a damping coefficient of approximately 15.1 lbf * s / in (26,440 Ns / cm) with a ratio of 4: 1 gears, (iii) a damping mechanism K having a damping coefficient of approximately 18.9 lbf * s / in (33.093 Ns / cm) with a gear ratio of 4: 1, (iv) a damping mechanism V having a damping coefficient of approximately 24.9 lbf * s / in (43.599 Ns / cm) with a gear ratio of 4: 1, (v) a damping mechanism G having a damping coefficient of approximately 25.1 lbf * s / in (43,950 Ns / cm) with a gear ratio of 6.25: 1, (vi) a mecanism or damping B having a damping coefficient of approximately 37.0 lbf * s / in (64,787 Ns / cm) with a gear ratio of 6.25: 1, (vii) a damping mechanism K having a coefficient of damping of approximately 46.2 lbf * s / in (80,896 Ns / cm) with a gear ratio of 6.25: 1, (viii) a damping mechanism V having a damping coefficient of approximately 60.7 lbf * s / in (106,285 Ns / cm) with a gear ratio of 6.25: 1, (ix) a damping mechanism G having a damping coefficient of approximately 164 lbf * s / in (287.16 Ns / cm) with a gear ratio of 16: 1, (x) a damping mechanism B that has a damping coefficient of approximately 242 lbf * s / in (423.74 N s / cm) with a gear ratio of 16 : 1, (xi) a damping mechanism K having a damping coefficient of approximately 303 lbf * s / in (530.55 N s / cm) with a gear ratio is 16: 1, (xii) a damping mechanism V having a damping coefficient of approximately 398 lbf * s / in (696.89 Ns / cm) with a gear ratio of 16: 1, and (xiii) an ideal flow rate in which the therapeutic agent is administered at a substantially constant rate.

Figure 33 shows that increasing the damping coefficient for the same gear ratio increases the administration time of the same volume of therapeutic agent. In some cases, increasing the damping coefficient makes the administration speed more linear. For example, for the 6: 25: 1 gear ratio, the highest damping coefficient of approximately 60.7 lbf * s / in (106.28 N s / cm) gives linear delivery speed than the damping coefficients plus low.

Figure 34 illustrates a graph of example torque pairs of the shock absorber (which can be extrapolated from the piston actuator travel) against damper speeds (in rpm) for model G, B, K, and V shock absorbers that have coefficients increasing damping. The points indicate the values of real force pairs and the dotted lines indicate the values of damping force pairs assumed by the manufacturer, which indicates that the values of the manufacturer were underestimated. The data indicates that the values of force pairs were substantially linear in the range between 0 and approximately 20 rpm. This is demonstrated by the high correlation coefficient for the linear adjustment equations shown in the graph. The use of the new linear adjustment equations for the torque of damping forces provided by the linear adjustment adjusts the damping coefficient and includes a static torque value. The replacement of these new values in a computer model allows a close approximation of the system response.

Since the static torque is multiplied by the gear ratio and subtracted directly from the force of the spring, it may be desired to choose the highest speed damper and the lowest gear ratio in an exemplary embodiment, for example, the model V damper and a 4: 1 gear ratio. Figure 35 illustrates a graph of the volume of therapeutic agent (in milliliters) versus time (in seconds) administered by different syringes by way of example using a model V buffer that has a damping coefficient of approximately 24.9 lbf * s / in (43.599 Ns / cm) and an example gear ratio of 4: 1.

After adjusting the computer models to reflect the torque of the measured shock absorber, a snail was designed to linearize the rate of administration of the therapeutic agent. Figure 36 illustrates a graph of the volume of therapeutic agent (in milliliters) administered and the diameter of the snail or cam coil (in inches) versus time (in seconds). Since the diameter of the snail changes during administration, the angular position data was integrated numerically along the spiral curve to give the linear position data of the plunger actuator at each data point.

Figure 36 shows that the actual measured administration rate is approximately 10% slower than that predicted by the model, but is almost constant as demonstrated by the high correlation coefficient (0.9995). The discrepancy between the measured and predicted data can be explained by inefficiencies in the gear, for example, areas where the gear is attached can be seen as sharp changes in the slope in the graph. The discrepancy can also be explained by the belt that couples the snail to the plunger actuator that is not perfectly in line with the plunger actuator, or the spring speed of the plunger actuator that is actually lower than the calculated one. Regardless of the source of the error, reducing the piston actuator spring speed by approximately 5% can produce an almost perfect correlation (1.0).

Different damping mechanisms were tested by way of example at different temperatures to determine the effect of temperature on the damping effect, that is, the linearity of the therapeutic agent administration. The torque of viscous rotating damping depends on the viscosity of the silicon grease inside the rotating damper. The viscosity of silicon grease depends in part on the temperature of the surrounding environment. Different damping mechanisms were also tested by way of example to determine the effect of manufacturing variability on the damping mechanisms on the damping effect, that is, the linearity of the administration of the therapeutic agent. Variations in the manufacture of the shock absorber can affect the pair of resistance forces provided by the shock absorber.

Figure 37 illustrates a graph of the volume of therapeutic agent (in milliliters) administered versus time (in seconds) achieved by: (i) a first buffer at room temperature, (ii) the first buffer at approximately 40 degrees Fahrenheit (4, 4 ° C) (in a refrigerator), (iii) a second shock absorber, (iv) the second shock absorber at approximately 0 degrees Fahrenheit (-17.8 ° C) (in a freezer), (v) a third shock absorber that has manufacturing variability with respect to the first and second shock absorbers, and (vi) a fourth shock absorber that has manufacturing variability with respect to the first and second shock absorbers.

Figure 37 shows that changes in temperature did not substantially affect the damping effect, that is, the linearity of the therapeutic agent administration. However, the administration speed was affected in some cases by lowering the temperature, for example, for the first buffer. Similarly, the manufacturing variability in the damping mechanisms did not substantially affect the damping effect, that is, the linearity of the therapeutic agent administration. However, the speed of administration was affected in some cases by manufacturing variability. Torque values of force torque varied approximately 5% in the sample group tested.

Thus, one or more factors can be configured to control the linearity and / or the rate of administration of the therapeutic agent which include, but are not limited to, the gear ratio, the damping coefficient, manufacturing deviations in the buffer, manufacturing deviations in the piston actuator, and the like. In addition, other characteristics of the plunger actuator can be varied to control the linearity and / or the flow rate of the therapeutic agent.

Figure 38 illustrates a schematic of a portion of an exemplary automatic injection device of the present disclosure 2600 employing a snail and an exhaust mechanism. The device 2600 includes a plunger drive mechanism to automatically operate a plug 2408 contained in a syringe or cartridge 2404. In the exemplary plunger drive mechanism, an out-of-control exhaust 2602 can be used to resist acceleration of the piston actuator 2406 providing linear damping. In the out-of-control exhaust 2602 by way of example, an exhaust wheel is provided having a plurality of teeth on its circumferential periphery and a vane is provided in the vicinity of the exhaust wheel. In an exemplary embodiment, the exhaust wheel may have 30 teeth, although by way of example the exhaust wheels are not limited to 30 teeth. The exhaust wheel can be coupled to coil 2426 by one or more gears that form a gear train. In an exemplary embodiment, a 50: 1 gear ratio can couple the coil 2426 to the exhaust wheel, but other example exhaust ratios can be used. The vane can have an adjustable mass moment of inertia as holes that can be presented with one or more pins, for example, steel centering pins.

In operation, when the torque is applied to the exhaust wheel, the exhaust wheel rotates and a tooth of the exhaust wheel confers a pair of driving forces on the vane so that the kinetic energy of the vane is reversed . The tooth pushes one arm of the palette aside. This causes the vane to oscillate, which releases the tooth of the exhaust wheel, simultaneously bringing the alternate arm of the vane towards interference with a second tooth of the exhaust wheel. As such, as the exhaust wheel rotates, its movement stops by the periodic impact with the vane, thus allowing the exhaust wheel to rotate only when the vane is free to swing. As the torque applied to the exhaust wheel increases, the exhaust wheel gives a stronger impulse to the vane, thereby increasing the speed of oscillation of the vane and, therefore, allowing the exhaust wheel to move more quickly

Assuming that the collisions between the teeth of the exhaust wheel and the blade are perfectly elastic, the blade absorbs, for each impact:

The power dissipation of the vane is directly proportional to the frequency of oscillation of the vane or> because two collisions occur between the exhaust wheel and the vane for each oscillation of the vane. So:

Assuming a pulse time of zero, since the collisions are perfectly elastic, it can be assumed that the magnitude of the angular velocity 0 "is constant and is related to 0max, the angular distance between collisions (in radians) can be represented by:

So,

The rotational speed of the exhaust wheel 9 is related to the number of teeth n and the oscillation frequency w and can be represented as:

So,

^{Since P = C} 992 ^{for a viscous rotating damper:}

which creates a nonlinear differential equation.

In another exemplary plunger drive mechanism, a Swiss anchor escape can be used to resist acceleration of the plunger actuator. Assuming a coordinate system in which 0 = 0 is in the balance of a coil spring attached to a balance wheel. If the damping is negligible in this system, then:

Where k is the torsional spring constant of the coil spring and J is the moment of mass of inertia:

Where r is the distance of the center of rotation and m is the mass, the natural frequency of the system is:

If the exhaust wheel has n teeth and a speed reduction spur gear train N couples the exhaust wheel to a coil of diameter D, then the coil rotates at angular speed:

Taking the derivative of the equation that relates 0 to x:

remains:

^2x

^{é =} D

So,

The components illustrated in Figure 38 that are common to Figure 24 are described with reference to Figure 24.

Figure 39 illustrates an exemplary piston drive mechanism 3900 that employs one or more linear deflection mechanisms to provide a force to eject a therapeutic agent from the cylinder portion 3902 of an automatic portable injection device. Cylinder portion 3902 extends longitudinally between a proximal end and a distal end, and is configured to contain a dose of a therapeutic agent. A distal end of the cylinder portion 3902 is coupled to a syringe needle 3904. A cap 3906 is provided movably within the cylinder portion 3902 to seal the dose of the therapeutic agent. One or more linear springs 3908 are provided to provide a deflecting force on the cap 3906 to move the cap 3906 inside the cylinder portion 3902 toward the syringe needle 3904 during an injection in an injection state. A distal end of the linear spring 3908 is in proximity to and / or in contact with a plunger 3916 having a plurality of teeth configured for engagement with a damping mechanism. The piston 3916 may be provided in the vicinity of and / or in contact with a distal end of a force transmission mechanism, for example, one or more ball bearings 3910.

A distal end of the ball bearings 3910 may also be in proximity to and / or in contact with the plug 3906 so that the deflection force of the spring 3908 is transmitted to the plug 3906 through the ball bearings 3910. Ball bearings 3910 can be enclosed in an enclosed rail 3912 that restricts the lateral or sideways movement of ball bearings 3910. That is, the deflection force of spring 3908 causes the piston 3916 and, in turn, the bearings of ball 3910 move substantially in a backward or forward mode, that is, toward or away from the plug 3906. The use of ball bearings 3910 allows the redirection of the deflection force to the plug 3906 and allows the minimization of the size Of the device. When operated, the spring 3908 exerts a deflecting force in the direction of the plug 3906. The deflection force is transmitted by the piston 3916 and the ball bearings 3910 to the cap 3906 and causes the cap 3906 to move towards the syringe needle 3904 inside the cylinder portion 3902. This causes the therapeutic agent to be ejected through of syringe needle 3904 outside the cylinder portion 3902.

A damping mechanism 3914, for example, a rotating viscous damper, can be provided and associated with spring 3908 and / or plunger 3916 to regulate the rate of administration of the therapeutic agent. The shock absorber 3914 may include a hub and a plurality of teeth that extend radially around the hub. The teeth of the shock absorber 3914 can be configured for engagement with the teeth of the piston 3916. The shock absorber 3914 can provide a force proportional to the movement speed of the piston 3916 to regulate the delivery speed. As such, the exemplary system 3900 can be used to provide the slow controlled release of the therapeutic agent by configuring the force provided by the spring 3908 and / or the properties of the damper 3914.

Figure 40 illustrates an exemplary piston drive mechanism 4000 that employs one or more clock springs to provide a force to a plug in a cylinder portion to expel a therapeutic agent from the cylinder portion. A deflection means 4002 is provided by a helical compression coil spring characterized by spring coils of progressively increasing diameter, so that when the spring is compressed, the coils nest inside each other in the manner of a clock spring , thus occupying the minimum space. A portion of the spring 4002 is in proximity to and / or in contact with a mechanical exhaust mechanism 4004 so that the rotational deflection force of the spring 4002 becomes a linear displacement of the mechanical exhaust mechanism 4004. The exhaust mechanism mechanical 4004 may be in proximity to and / or in contact with the plug so that the deflection force of the spring 4002 is transmitted as a linear displacement to the plug through the movement of the mechanical exhaust mechanism 4004. That is, the force The deflection of the spring 4002 causes the mechanical exhaust mechanism 4004 to move substantially in a rearward or forward fashion, that is, towards or away from the plug. The use of the mechanical exhaust mechanism 4004 allows the redirection of the deflection force to the plug and allows the minimization of the size of the device.

When actuated, the spring 4002 exerts a deflection force that becomes a force back and forth through the mechanical exhaust mechanism 4004 in the direction of the plug. The deflection force is transmitted directly or indirectly to the cap and causes the cap to move towards the needle within the cylinder portion. This causes the therapeutic agent to be ejected through the needle outside the cylinder portion. As such, the exemplary system 4000 may be used to provide the slow controlled release of the therapeutic agent by configuring the force provided by the spring 4002 and / or the linear displacement provided by the mechanical exhaust mechanism 4004. The mechanical exhaust mechanism 4004 can be configured to control, for example, the amount of feed per cycle. Spring 4002 can be sized to predominate over adhesion-slip forces.

Figures 41 and 42 illustrate an exemplary automatic injection device of the present disclosure 4100 that employs a fluid-based plunger drive mechanism in which fluid pressure and / or movement of a working fluid are used. to move a cap into the cylinder portion of a syringe or cartridge. The plunger drive mechanism includes one or more fluid circuits to provide a force to a cap for expelling a dose of a therapeutic agent from a cylinder portion 4104 of a syringe or cartridge. Figure 41 is a schematic of the automatic injection device 4100 by way of example and Figure 40 is a perspective view of the automatic injection device 4100 by way of example. The automatic portable injection device 4100 may include a pressure element 4106 that stores an incompressible working fluid that provides a fluid pressure. Exemplary working fluids may include, but are not limited to, water, air, oil, and the like. Exemplary pressure elements 4106 may include, but are not limited to, an elastic vesicle, a master cylinder, a loaded spring syringe, and the like.

The pressure element 4106 can be coupled to a flow restrictor 4108 by a pipe 4110. The flow limiter 4108 can restrict the flow of the working fluid so that the fluid pressure upstream of the flow limiter is greater than the pressure of fluid downstream of the flow restrictor. The flow restrictor 4108 may include an orifice of diameter ranging from about 0.001 inches (0.00254 cm) to about 0.01 inches (0.0254 cm), but the diameters of the flow restrictor holes by way of example they are not limited to this interval as an example. The orifice of the flow restrictor 4108 may have lengths ranging from about 10 mm to about 50 mm, but the lengths of the flow restrictor holes by way of example are not limited to this range by way of example.

The exemplary embodiments of the present disclosure may configure various features of the administration system to control the total administration time of the therapeutic agent. The exemplary embodiments of the present disclosure can also configure various features of the delivery system based on the viscosity of the working fluid and / or the therapeutic agent. Exemplary features may include, but are not limited to, the diameter of the hole, the length of the hole, the viscosity of the working fluid, and the like. For example, the diameter of the flow restrictor orifice can be decreased to increase the total administration time.

The flow restrictor 4108 can also be coupled to the cap by a pipe 4112. When the working fluid is released from the pressure element 4106 by the flow limiter 4108, the pressure of the working fluid fluid drives the plug forward into the cylinder portion 4104 for expelling the dose of the therapeutic agent from the cylinder portion 4104.

In an exemplary embodiment of the present disclosure, prior to an injection in a pre-injection state, the working fluid may not be released from the pressure element 4106. In this exemplary embodiment, an activator of the administration (not shown) to the pressure element 4106 so that, after activation of the administration activator, the working fluid is released from the pressure element 4106 in the pipes 4110 and 4112. The fluid pressure of the working fluid advances the cap within the cylinder portion 4104, thus injecting the dose into the patient's skin. Thus, the fluid circuit established by the flow of the working fluid and the flow limiter can provide a regulated force to the plug.

In an exemplary embodiment of the present disclosure, the dose is administered in a linear administration profile, that is, at a substantially constant rate of administration. The linearity of the administration profile can be achieved by the high pressure of the working fluid provided by the pressure element 4106 upstream of the flow limiter 4108 and the damping effect provided by the flow limiter 4108. The pressure upstream of the limiter Flow rate 4108 can be maintained at a high level with respect to the projected adhesion-slip forces so that a highly damped system is achieved. In order for the plug to move forward within the cylinder portion 4104, the plug would need to remove a vacuum in the working fluid between the flow restrictor 4108 and the cylinder portion 4104, which is difficult to achieve to an appreciable degree because that the working fluid is essentially incompressible.

The damped hydraulic delivery circuits by way of example allow the movement of the cap by volumetric dosing, instead of by a direct application of force, thus minimizing adhesion-slip phenomena in the administration profile of the therapeutic agent.

In an exemplary embodiment of the present disclosure, an exemplary volume of 0.8 milliliters of therapeutic agent may be administered at an exemplary administration pressure of approximately 16.5 psi (1.15 kg / cm2) within an exemplary duration of approximately 12 minutes. In another exemplary embodiment, an exemplary volume of 0.8 milliliters of therapeutic agent may be administered at an exemplary administration pressure of approximately 5 psi (0.35 kg / cm 2) within a duration by way of example of approximately 17 minutes.

Figure 43 illustrates a graph of the cumulative amount of therapeutic agent (in grams) versus time (in seconds) as administered by an exemplary administration system at an exemplary administration pressure of approximately 16.5 psi (1.15 kg / cm2). Figure 44 illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) versus time (in seconds) as administered by an exemplary administration system that includes a first example flow limiter having a diameter by way of example of about 0.008 inches (0.020 cm) and an exemplary length of about 34.3 mm. The total administration time to administer approximately 1 milliliter of a therapeutic agent was approximately twenty seconds. Figure 45 illustrates a graph of the cumulative volume of therapeutic agent (in milliliters) versus time (in seconds) as administered by an exemplary administration system that includes a second example flow limiter having a diameter by way of example of about 0.002 inches (0.005 cm) and an exemplary length of about 34.3 mm. The total administration time to administer approximately 1 milliliter of a therapeutic agent was approximately 15 minutes. In the illustrative graphs, the administration profile is substantially linear, that is, substantially constant over time, and does not show an initial bolus or abrupt change or inflection representative of inconsistent administration rates.

Figure 46 is a schematic drawing of an exemplary automatic injection device 4600 that employs one or more fluid circuits to provide a force to eject a therapeutic agent from a cartridge assembly. Figure 47 is a top view of the device 4600 by way of example. The exemplary automatic injection device 4600 includes a cylinder portion 4602 containing a dose of a therapeutic agent. A distal end of the cylinder portion 4602 is provided in the vicinity of or coupled to a syringe needle (hidden by a needle cover 4604) that is protectively covered by a needle cover 4604. The device 4600 includes an injection button that includes a partition and carries an injection needle (not shown). In an exemplary embodiment, the device 4600 may include an injection needle holder 4606 to contain the injection needle. In an exemplary embodiment, the injection needle can be extended substantially orthogonally to the plane of the device as illustrated, and can be held in place by the needle holder 4606. A needle lock 4608 can be provided to prevent that the injection needle comes out of the housing once attached and can be located in the housing near the injection needle.

In an exemplary embodiment of the present disclosure, a syringe or cartridge actuator 4610 can be provided to advance the cylinder portion 4602 within the housing toward the partition. It can provide an activator for activation of the syringe or cartridge actuator 4610, for example, when the injection button is pressed or when the needle cover 4604 is removed.

In this exemplary embodiment of the present disclosure, a master cylinder 4612 is provided which contains a working fluid to provide a fluid pressure to actuate a plug 4614 within the cylinder portion 4602. The master cylinder 4612 can be coupled to an administration activator 4616 which, when activated, releases the working fluid in fluid communication with the plug 4614 and allows the fluid pressure to advance the plug 4614 into the cylinder portion 4602.

The exemplary embodiments of the present disclosure also provide needle retraction systems for retracting an injection needle from a vertically lowered position (or an extended or deployed position) outside the device housing in the region of contact with the device. patient to a vertically raised position (or a retracted position) inside the device housing. The automatic portable injection device 4600 includes a retraction mechanism that automatically raises the injection button from a vertically pressed position inside the housing during an injection in an injection state to a vertically raised position inside the housing in a post-state. injection after an injection. In an exemplary embodiment, the retraction mechanism may be a telescopic element. The master cylinder 4612 can be coupled to a retraction activator which, when activated, releases the working fluid in fluid communication with the retraction activator and allows the fluid pressure to activate the retraction mechanism.

Figure 48 illustrates a top view of the device 4600 showing a conduit 4802 that couples the master cylinder 4612 to a flow limiter 4804, a conduit 4806 that couples the flow limiter 4804 to the plug in the cylinder portion of the device, and a conduit 4808 that couples the master cylinder 4612 to a retraction mechanism 4810 by means of a valve 4812, for example, a control valve. Figure 49 illustrates a schematic diagram of device 4600.

The control valve 4812 may have a suitable opening pressure at which or above which the control valve 4812 allows fluid in the conduit 4808 coupled to the retraction mechanism 4810. In an exemplary embodiment, the pressure opening is greater than the maximum fluid pressure in conduit 4806 required to drive the plug during an injection in an injection state. Otherwise, undesirably, the needle retraction process can begin during or even before injection. In an exemplary embodiment, the pressure in the conduit 4806 at the end of the movement of the cap during an injection in an injection state is greater than the opening pressure. Otherwise, at the end of the movement of the cap, the pressure in the conduit 4808 may be insufficient to activate the retraction mechanism 4810. The volume of the working fluid in the master cylinder 4612 is sufficient to administer the entire dose of the therapeutic agent and to activate the retraction mechanism 4810.

In an exemplary embodiment of the present disclosure, the retraction mechanism 4810 and the control valve 4812 can be provided separately. In another exemplary embodiment, the retraction mechanism 4810 and the control valve 4812 can be provided as a single element, for example, as an inversion diaphragm.

Figure 50 illustrates a graph of the pressure after the control valve and behind the plug (in psi) versus time (in seconds) in an exemplary embodiment. In an exemplary embodiment, the opening pressure of the control valve may be approximately 7.5 psi (0.527 kg / cm2) and the diameter of the flow restrictor orifice may be approximately 0.008 inches (0.020 cm).

During an injection in an injection state, the flow restrictor 4804 may cause the pressure in the conduit 4802 to be approximately 10 to approximately 15 psi (0.703 - 1.054 kg / cm2), while the pressure in the conduit 4806 may be approximately 5 to about 6 psi (0.351-0.421 kg / cm2). The control valve 4812 thus prevents any flow of the working fluid from entering the conduit 4808 while the cap is moving during injection. Once the cap stops moving at the end of the injection, that is, when the dose has been completely expelled from the cylinder portion, the pressure in the conduit 4806 increases beyond 7.5 psi (0.527 kg / cm2). This causes the control valve 4812 to open, allowing the working fluid to circulate in the conduit 4808 that activates the retraction mechanism 4810. The retraction mechanism 4810 in turn unlocks the needle lock and retracts the injection button / carrier 4606 carrying the injection needle. Because it is based on the equalization of the pressure in the hydraulic circuit, the needle retraction process ensures that the entire dose is administered before the injection needle is retracted, maximizes the use of the therapeutic agent and minimizes overfilling required in cylinder portion 4602.

Any suitable activating mechanism can be used to activate the needle retraction systems. In an exemplary embodiment, the activating mechanism can automatically activate the needle retraction system when the portable automatic injection device moves from an injection state to a post-injection state. In an exemplary embodiment, the end of the administration of a therapeutically effective dose of the therapeutic agent can activate the needle retraction system. In another embodiment by way of example, removal of the patient device before the end of the administration of a therapeutically effective dose of the therapeutic agent can activate the needle retraction system. In another exemplary embodiment, the needle retraction system can be manually activated by a user.

Figure 51 illustrates a side view of an exemplary automatic injection device 5100 in which the housing 5102 of the portable automatic injection device 5100 includes a skin sensor foot 5104, which is a structure in an exemplary embodiment housed below or in the housing portion 5102 proximal to the injection site. In an exemplary embodiment, prior to injection of the therapeutic agent and during injection, the skin sensing foot 5104 is retained within or forms a portion of the bottom of the housing 5102. When the portable automatic injection device 5100 joins the injection site and is activated, the skin sensor foot 5104 may be free to move, but may be restricted by the injection site. In an exemplary embodiment, when the automatic portable injection device 5100 is removed from the injection site, regardless of whether drug administration was completed, the skin sensor foot 5104 is no longer restricted, and extends and projects out from the periphery of the housing 5102. This, in turn, activates a retraction activator. When the retraction activator is activated, a retraction mechanism retracts the injection needle which can also raise the injection button from the vertically lowered position to the vertically raised position, so that the injection button protrudes from the top of the housing 5102 and the injection needle retracts into the housing 5102.

V. Example needle protection systems

The exemplary embodiments of the present disclosure provide different exemplary needle protection systems for maintaining the injection needle within the portable automatic injection device in a post-injection state after an injection. Needle protection prevents accidental needle sticks from injuring the patient or any other human being in the vicinity of the portable automatic injection device.

Figures 52A and 52B illustrate an exemplary needle protection system 5200 that maintains an injection needle 5202 in a retracted position within a housing 5204 of an automatic injection system. The injection needle 5202 is mobile with respect to the housing 5204 away from or towards the patient's skin. When the needle 5202 is in a position within the housing 5204 further away from the patient's skin, the needle 5202 is in a retracted position and does not protrude outside the housing 5204. When the needle 5202 is in a position within the housing 5204 closest to the patient's skin, the needle 5202 is in an inserted or deployed position and protrudes completely or partially from the housing 5204. The housing 5204 can be provided with an opening 5206 through which the needle 5202 can protrude out of housing 5204.

The needle protection system 5200 employs a barrier mechanism 5208 that prevents the needle 5202 from protruding from the housing 5204 in a pre-injection state before an injection and in a post-injection state after an injection when the needle 5202 It is in the retracted position. Figure 52A illustrates the system 5200 in which the needle 5202 is in an inserted or deployed position and protrudes completely or partially through the opening 5206 outside the housing 5204, for example, during an injection in an injection state. In this case, the barrier mechanism 5208 moves away from the opening 5206 so that the opening 5206 is open to the outside of the housing 5204, and the needle 5202 is free to protrude through the opening 5206 to the outside of the housing 5204. Figure 52B illustrates the 5200 system in which the needle 5202 is in a retracted position and does not protrude from the housing 5204, for example, in a pre-injection state and a post-injection state. In this case, the barrier mechanism 5208 is aligned with and covers the opening 5206 so that the opening 5206 is no longer open to the outside of the housing 5204, and the needle 5202 is not free to protrude through the opening 5206 to the outside the housing 5204. In an exemplary embodiment, the barrier mechanism 5208 can be rotatably rotated about a rotation point between a first position in which the opening 5206 (in Figure 52A) is exposed and a second position in which it covers the opening 5206 (in Figure 52B).

Figures 53A and 53B illustrate another exemplary needle protection system 5300 provided in the housing 5302 of an automatic injection system. The automatic injection system includes an injection needle 5304 that is mobile with respect to the housing 5302 away from or towards the patient's skin. When the needle 5304 is in a position within the housing 5302 further away from the patient's skin, the needle 5304 is in a retracted position and does not protrude outside the housing 5302. When the needle 5304 is in a position within the housing 5302 closest to the patient's skin, the needle 5304 is in an inserted or deployed position and protrudes completely or partially from the housing 5302.

The needle protection system 5300 includes a needle locking sleeve 5306 provided in the vicinity of the injection needle 5304 to block the injection needle in the retracted position in a pre-injection state and a post-injection state. The needle locking sleeve 5306 can be coupled to a bolt 5308 disposed in a groove 5310. The bolt 5308 may be in a first position (illustrated in Figure 53A) with respect to the groove 5310 in which the locking sleeve of the needle 5306 blocks the injection needle 5304 in the retracted position inside the housing 5302. The bolt 5308 may be in a second position (illustrated in Figure 53B) with respect to the groove 5310 in which the locking sleeve of the needle 5306 allows the injection needle 5304 to protrude out of the 5302 housing.

In an exemplary embodiment of the present invention, an early withdrawal retraction activator 5312 which, when activated, activates a retraction mechanism that retracts the injection needle 5304 into the housing 5302. The retraction activator of Early withdrawal 5312 can be activated when the automatic portable injection device 5300 is removed from the injection site before the therapeutically effective dose of therapeutic agent is fully administered. In an exemplary embodiment, the early withdrawal retraction activator 5312 may include a latch 5314, for example, a flexible plastic hook, which is released after removal of the portable automatic injection device 5300 from the injection site. Figure 53A shows the early withdrawal retraction activator 5312 in which the latch 5314 is coupled to a portion of the closure sleeve 5306 when the portable injection device is coupled to the injection site. Figure 53B shows the early withdrawal retraction activator 5312 in which the latch 5314 is released from the portion of the closure sleeve 5306 when the portable injection device is removed from the injection device. The release of latch 5314 from the portion of the closing sleeve 5306 activates the retraction mechanism. An exemplary retraction mechanism may be sensitive to an end-of-dose retraction activator and sensitive to the early withdrawal retraction activator 5310 to automatically retract the injection needle 5304 from the injection site.

Figure 54 illustrates an exemplary needle protection system 5400 that maintains an injection needle held by an injection carrier 5402 in a retracted position within a housing 5404 of an automatic injection system. The injection needle is mobile with respect to the housing 5404 away from or towards the patient's skin. When the injection needle is in a position within the housing 5404 further away from the patient's skin, the needle is in a retracted position and does not protrude outside the housing 5404. When the needle is in a position within the housing 5404 closer to the patient's skin, the needle is in an inserted or deployed position and protrudes completely or partially from the housing 5404. The housing 5404 can be provided with an opening through which the needle can protrude out of the housing 5404 .

The needle protection system 5400 includes a needle lock 5408 provided in the vicinity of or in contact with the needle holder 5402. In an exemplary embodiment, the needle lock 5408 may be a pivoting member. or pivot that can pivot or rotate around a pivot point or interface. A needle lock release mechanism 5410 may be provided in the vicinity of or in contact with the needle lock mechanism 5408. The needle lock release mechanism 5410 may be in a first position when the injection needle is in a vertically lowered position and protrudes out of the 5404 housing (in an injection state), and in a second position when the injection needle is in a vertically raised or retracted position within the 5404 housing (in a pre-injection state or a post-injection state)

When the needle lock release mechanism 5410 is in the first position (i.e., when the injection needle is in a vertically lowered injection position), the needle lock 5408 may be in an unlocked position in which does not block the injection needle in the vertically raised position in the housing 5404. Alternatively, the needle lock 5408 may be in a locked position where it blocks the injection needle 5408 in the position vertically lowered in the housing 5404. In an exemplary embodiment (i.e., when the injection needle is in a vertically lowered injection position), the retraction of the injection needle and / or the needle holder 5402 to the vertically raised position within the housing 5404 can activate the needle lock release mechanism 5410, that is, move the release mechanism from the first position to the second position. When the needle lock release mechanism 5410 moves to the second position, the needle lock 5408 can pivot or rotate, thereby blocking the injection needle and / or the needle holder 5402 in the vertically raised position in 5404 housing.

Figure 55 illustrates an exemplary needle protection system 5500 that maintains an injection needle held by an injection carrier 5502 in a retracted position within a housing 5504 of an automatic injection system. The injection needle is mobile with respect to the housing 5504 away from or towards the patient's skin. When the injection needle is in a position within the housing 5504 further away from the patient's skin, the needle is in a retracted position and does not protrude outside the housing 5504. When the needle is in a position within the housing 5504 closer to the patient's skin, the needle is in an inserted or deployed position and protrudes completely or partially from the housing 5504. The housing 5504 can be provided with an opening through which the needle can protrude out of the housing 5504 .

The needle protection system 5500 includes a needle lock 5508 provided in proximity to or in contact with the needle holder 5502. In an exemplary embodiment, the needle lock 5508 may be a pivoting member. or pivot that can pivot or rotate around a pivot point or interface. The needle lock 5508 may include a deflection mechanism 5506 that applies a rotational spring force to the needle holder 5502 about a longitudinal axis of the deflection mechanism. In an exemplary embodiment, the needle lock 5508 can be provided symmetrically around the needle holder 5502 so that the rotational force is applied by the diversion mechanism 5506 substantially symmetrically around the needle holder 5502

A needle lock release mechanism 5510 may be provided in proximity to or in contact with the needle lock 5508. The needle lock release mechanism 5510 may be in a first position when the injection needle is in a vertically lowered position and protrudes outside the housing 5504 (in an injection state), and in a second position when the injection needle is in a vertically raised or retracted position inside the housing 5504 (in a pre-injection state or a post injection state)

When the needle lock release mechanism 5510 is in the first position (i.e., when the injection needle is in a vertically lowered injection position), the deflection mechanism 5506 can apply a spring force to the holder of the needle 5502 in the clockwise direction towards the patient's body so that the needle holder 5502 is held in the vertically lowered position. When the needle lock release mechanism 5510 is in the second position (i.e., when the injection needle is in a vertically raised pre- or post-injection state), the deflection mechanism 5506 can apply a spring force to the needle holder 5502 in the direction counterclockwise away from the patient's body so that the needle holder 5502 is raised and held in the vertically raised position.

In an exemplary embodiment of the present disclosure, retraction of the injection needle and / or needle holder 5502 to the vertically raised position within the housing 5504 can activate the needle lock release mechanism 5510 , that is, move the release mechanism from the first position to the second position. When the mechanism for releasing the needle lock 5510 moves to the second position, the needle lock 5508 can pivot or rotate under the force of the deflection member 5506 in the direction counterclockwise. of the patient's body, thereby blocking the injection needle and / or needle holder 5502 in the vertically raised position in the housing 5504.

SAW. Therapeutic agents for use in automatic injection devices by way of example

Automatic exemplary injection devices can be used to administer essentially any therapeutic substance or agent that is suitable for injection administration. Normally, the therapeutic substance or agent will be in a fluid form, for example, liquid, although medications in other forms such as gels or semi-solids, suspensions, particle solutions, etc., may also be suitable for use if the device Automatic portable injection is designed to allow the administration of such medication form.

Preferred medications are biological agents, such as antibodies, cytokines, vaccines, fusion proteins and growth factors. Methods of antibody preparation have been described above.

Non-limiting examples of other biological agents that can be used as medication in the automatic injection device include, but are not limited to, antibodies to or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-1. , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, IL-21, IL-23, interferons , EMAP-II, GM-CSF, FGF and PDGF; antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or their ligands that include CD154 (gp39 or CD40L); TNFa converting enzyme inhibitors (TACE); IL-1 inhibitors (interleukin-1 converting enzyme inhibitors, IL-1RA, etc.); interleukin 11; IL-18 antagonists that include IL-18 antibodies or soluble IL-18 receptors, or IL-18 binding proteins; non-suppressive anti-CD4 inhibitors; CD80 (B7.1) or CD86 (B7.2) costimulant pathway antagonists that include antibodies, soluble receptors or antagonist ligands; agents that interfere with signaling by inflammatory procytokines such as TNFa or IL-1 (for example, IRAK, NIK, IKK, p38 kinase inhibitors or MAP); IL-1 converting enzyme (ICE) inhibitors; T lymphocyte signaling inhibitors such as kinase inhibitors; metalloproteinase inhibitors; angiotensin converting enzyme inhibitors; soluble cytokine receptors and their derivatives (for example, soluble p55 or p75 TNF receptors and p75TNFRIgG derivatives (Enbrel ™ and p55TNFRIgG (Lenercept)), sIL-1RI, sIL-1RII, sIL-6R); anti-inflammatory cytokines (for example, IL-4, IL-10, IL-11, IL-13 and TGF-beta); Rituximab; IL-1 TRAP; MRA; CTLA4-Ig; IL-18 BP; anti-IL-18; anti-IL15; IDEC-CE9,1 / SB 210396 (non-suppressive primed anti-CD4 antibody; IDEC / SmithKline; see for example, Arthritis & Rheumatism (1995) Vol. 38; S185); DAB 486-IL-2 and / or DAB 389-IL-2 (fusion proteins of ^{i L-2;} Seragen; see, for example, Arthritis & Rheumatism (1993) Vol. 36; 1223); Anti-Tac (humanized anti-IL-2Ra; Protein Design Labs / Roche); IL-4 (anti-inflammatory cytokine; ADNX / Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX / Schering); IL-10 and / or IL-4 agonists (eg, agonist antibodies); IL-1RA (IL-1 receptor antagonist; Synergen / Amgen); anakinra (Kineret® / Amgen); TNF-bp / s-TNF (soluble TNF binding protein; see for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S284; Amer. J. Physiol. - Heart and Circulatory Physiology (1995) 268: 37-42); R973401 (phosphodiesterase type IV inhibitor; see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S282); MK-966 (COX-2 inhibitor; see for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S81); Iloprost (see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S82); zap-70 and / or lck inhibitor (zap-70 or lck tyrosine kinase inhibitor); VEGF inhibitor and / or VEGF-R inhibitor (vascular endothelial cell growth factor inhibitors or vascular endothelial cell growth factor receptor; angiogenesis inhibitors); TNF-convertase inhibitors; antibodies anti-IL-12; anti-IL-18 antibodies; interleukin-11 (see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement), S296); interleukin-13 (see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement), S308); interleukin-17 inhibitors (see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement), S120); antithymocyte globulin; anti-CD4 antibodies; CD5-toxins; ICAM-1 antisense phosphorothioate oligodeoxynucleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell Sciences, Inc.); and anti-IL2R antibodies.

VII. TNFa inhibitors for use in automatic injection devices by way of example

According to an embodiment of the invention, the illustrative automatic injection device can be used to administer a dose of a TNF inhibitor used to treat arthritis and other diseases. In one embodiment, the solution content in the syringe contains 40 or 80 milligrams of medicine (TNFa blocker or inhibitor) / 1 ml, for example, 40 or 80 mg of adalimumab, 4.93 mg of sodium chloride, 0.69 mg dehydrated monobasic sodium phosphate, 1.22 mg dehydrated dibasic sodium phosphate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 50 and water for injection, with USP sodium hydroxide added as necessary to adjust the pH to be approximately 5.2.

The present invention can be used to administer a dose of a substance, such as a liquid drug, for example, a TNFa inhibitor, to a patient. In one embodiment, the dose administered by the automatic injection device of the invention comprises an antibody against human TNFa, or its antigen binding portion. In one embodiment, the TNF inhibitor used in the methods and compositions of the present disclosure includes isolated human antibodies, or their antigen binding portions, that bind to human TNFa with high affinity and a low dissociation constant, and have High neutralizing capacity Preferably, the human antibodies of the present disclosure are recombinant neutralizing human anti-TNFa antibodies, such as, for example, the recombinant neutralizing antibody called D2E7, also referred to as HUMIRA0 or adalimumab (Abbott Laboratories; the amino acid sequence of the VL region of D2E7 is shown in SEQ ID NO: 1 of US Patent No. 6,090,382, the amino acid sequence of the VH region of D2E7 is shown in SEQ ID ^{N or:} 2 of US Patent No. 6,090,382). The properties of D2E7 have been described in Salfeld et al., US Pat ^{. or u.} No. 6,090,382, 6,258,562 and 6,509,015. Other examples of TNFa inhibitors include chimeric and humanized murine anti-hTNFa antibodies that have undergone clinical trials for the treatment of rheumatoid arthritis (see, for example, Elliott et al. (1994) Lancet 344: 1125-1127; Elliot et al. (1994) Lancet 344: 1105-1110; and Rankin et al. (1995) Br. J. Rheumatol. 34: 334-342).

An anti-TNFa antibody (also referred to herein as a TNFa antibody), or its antigen binding fragment, includes chimeric, humanized and human antibodies. Examples of TNFa antibodies that can be used in the present disclosure include, but are not limited to, infliximab (Remicade®, Johnson and Johnson; described in U.S. Patent No. 5,656,272, incorporated herein by reference. document), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb (Peptech) and CNTO 148 (golimumab; Medarex and Centocor , see patent document WO 02/12502). Additional TNF antibodies that can be used in the present disclosure are described in US Pat. No. 6,593,458; 6,498,237; 6,451,983; and 6,448,380.

Other examples of TNFa inhibitors that can be used in the methods and compositions of the present disclosure include etanercept (Enbrel, described in WO 91/03553 and WO 09/406476), soluble type I TNF receptor, a Type I pegylated soluble TNF receptor (PEGs TNF-R1), p55TNFR1gG (Lenercept) and recombinant TNF binding protein (r-TBP-I) (Serono).

In one embodiment, the exemplary embodiments provide improved uses and compositions for treating a disorder in which TNFa is harmful, for example, rheumatoid arthritis, with a TNFa inhibitor, for example, a human TNFa antibody, or its portion of antigen binding, through an automatic portable injection device.

A TNFa inhibitor includes any agent (or substance) that interferes with the activity of TNFa. In a preferred embodiment, the TNFa inhibitor can neutralize TNFa activity, particularly harmful TNFa activity that is associated with disorders in which TNFa activity is harmful, including, but not limited to, rheumatoid arthritis, arthritis. juvenile rheumatoid, ankylosing spondylitis, Crohn's disease, psoriasis and psoriatic arthritis.

VIII. Pharmaceutical compositions for use in automatic injection devices by way of example Pharmaceutical compositions may be loaded into the automatic injection device of the invention for administration to a patient. In one embodiment, the antibodies, antibody portions, as well as other TNFa inhibitors, can be incorporated into pharmaceutical compositions suitable for administration to a patient using the device of the invention. Typically, the pharmaceutical composition comprises an antibody, antibody portion, or other TNFa inhibitor, and a pharmaceutically acceptable carrier. "Vehicle Pharmaceutically acceptable "includes each and every solvent, dispersion media, coatings, antibacterial and antifungal agents, isotonic and delayed absorption agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as their combinations.In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride, in the Composition Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the storage stability or efficacy of the antibody, antibody portion, or other TNFa inhibitor.

The compositions for use in the methods and compositions of the present disclosure may be in a variety of forms according to administration by the device of the invention, including, for example, liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions. In a preferred embodiment, the antibody or other TNFa inhibitor is administered by subcutaneous injection using the device of the invention. In one embodiment, the patient is administered the TNFa inhibitor, which includes, but is not limited to, TNFa antibody, or its antigen binding portion, to itself using the device of the invention.

The therapeutic compositions should normally be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other suitable ordered structure at high drug concentration. Sterile injectable solutions can be prepared by incorporating the active compound (ie, the antibody, antibody portion, or other TNFa inhibitor) in the amount required in an appropriate solvent with one or a combination of the components listed above, as required, followed by sterilization by filtration. Generally, the dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the other required components of those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization which gives a powder of the active ingredient plus any additional desired component of its solution previously sterilized by filtration. The proper fluidity of a solution can be maintained, for example, using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and using surfactants. Prolonged absorption of the injectable compositions can be caused by including in the composition an agent that delays absorption, for example, monostearate and gelatin salts.

In one embodiment, the exemplary embodiments of the present disclosure provide an automatic portable injection device, for example, a self-injector pen, comprising an effective TNFa inhibitor and a pharmaceutically acceptable carrier. Thus, the present disclosure provides an automatic prechargeable and / or preloaded injection device comprising a TNFa inhibitor.

In one embodiment, the antibody or antibody portion for use in the methods of the present disclosure is incorporated into a pharmaceutical formulation as described in patent document PCT / IB03 / 04502 and US Pat. No. 2004/0033228. This formulation includes a 50 mg / ml concentration of D2E7 antibody (adalimumab), in which an automatic portable injection device contains 40 mg of antibody for subcutaneous injection. In one embodiment, the automatic injection device of the present disclosure (or more specifically the device syringe) comprises a formulation of adalimumab having the following formula: adalimumab, sodium chloride, monobasic sodium phosphate dihydrate, dibasic sodium phosphate dihydrate, sodium citrate, citric acid monohydrate, mannitol, polysorbate 80 and water, for example, water for injection. In another embodiment, the automatic injection device comprises a volume of adalimumab that includes 40 mg of adalimumab, 4.93 mg of sodium chloride, 0.69 mg of monobasic sodium phosphate dihydrate, 1.22 mg of dibasic sodium phosphate dihydrate , 0.24 mg of sodium citrate, 1.04 mg of citric acid monohydrate, 9.6 mg of mannitol, 0.8 mg of polysorbate 80 and water, for example, water for injection. In one embodiment, sodium hydroxide is added as necessary to adjust the pH.

The dose amount of the TNFa inhibitor in the automatic injection device may vary depending on the disorder for which the TNFa inhibitor is used for treatment. In one embodiment, the present disclosure includes an automatic portable injection device comprising a dose of adalimumab of about 20 mg of adalimumab; 40 mg adalimumab; 80 mg adalimumab; and 160 mg adalimumab. It should be noted that for all ranges described herein, which include dose ranges, all intermediate numbers to the cited values are included in the present disclosure, for example, 36 mg of adalimumab, 48 mg of adalimumab, etc. . In addition, the ranges cited using such numbers are also included, for example 40 to 80 mg of adalimumab. The numbers cited in this document are not intended to limit the scope of this disclosure.

TNFa antibodies and inhibitors used in the present disclosure can also be administered in the form of protein crystal formulations that include a combination of encapsulated protein crystals within a polymeric vehicle to form coated particles. The coated particles of the protein crystal formulation may have a spherical morphology and be microspheres of up to 500 micrometers in diameter or they may have some other morphology and be microparticles. The enhanced concentration of protein crystals allows The antibody of the present disclosure is administered subcutaneously. In one embodiment of the present disclosure, the TNFa antibodies of the present disclosure are administered by a protein delivery system, in which one or more of a protein crystal formulation or composition is administered to a patient with a disorder related to TNFa. Compositions and methods of preparing stabilized formulations of whole antibody crystals or antibody fragment crystals are also described in WO 02/072636.

In one embodiment, a formulation comprising the crystallized fragments of the antibodies described in International Patent Application No. PCT / IB03 / 04502 and U.S. Patent Publication. No. 2004/0033228 is used to treat rheumatoid arthritis using the methods of the present disclosure.

Complementary active compounds can also be incorporated into the compositions. In certain embodiments of the present disclosure, an antibody or antibody portion for use in the methods of the present disclosure is co-formulated with and / or co-administered with one or more additional therapeutic agents, including an inhibitor or antagonist. of rheumatoid arthritis. For example, an anti-hTNFa antibody or antibody portion may be co-formulated and / or co-administered with one or more additional antibodies that bind to other targets associated with TNFa-related disorders (eg, antibodies that bind to other cytokines or that bind to cell surface molecules), one or more cytokines, soluble TNFa receptor (see, for example, PCT Publication No. WO 94/06476) and / or one or more chemical agents that inhibit the production or activity of hTNFa (such as cyclohexane-ilidene derivatives as described in PCT Publication No. WO 93/19751) or any combination thereof. In addition, one or more antibodies of the present disclosure may be used in combination with two or more of the above therapeutic agents. Said combination therapies can advantageously use lower dosages of the therapeutic agents administered, thus avoiding possible side effects, complications or the low level of response by the patient associated with the various monotherapies. Additional agents that can be used in combination with a TNFa antibody or antibody portion are described in US Pat. No. 11/800531.

X. Equivalents

In the description of the exemplary embodiments, specific terminology is used for reasons of clarity. For the purpose of description, each specific term is intended to include at least all technical and functional equivalents that operate in a similar manner to achieve a similar purpose. In addition, in some cases where a particular exemplary embodiment includes a plurality of system elements or method steps, the elements or stages may be replaced with a single element or stage. Likewise, a single element or stage can be replaced with a plurality of elements or stages that serve the same purpose. In addition, where parameters for various properties are specified herein for exemplary embodiments, the parameters can be adjusted up or down by 1/20, 1/10, 1/5, 1/3, ^ , etc., or by its rounded approximations, unless otherwise specified. Furthermore, although exemplary embodiments have been shown and described with reference to their particular embodiments, those skilled in the art will understand that various substitutions and alterations in form and details can be made therein without departing from the scope of the invention.

Exemplary flowcharts are provided herein for illustrative purposes and are non-limiting examples of methods. One of ordinary skill in the art will recognize that exemplary methods may include more or less stages than those illustrated in the example flowcharts, and that the steps in the exemplary flowcharts can be performed in A different order than shown.

Claims (1)

1. An automatic portable injection device (100, 600, 1800, 2400, 2800, 4100, 5100) free of a battery to provide a subcutaneous injection of a therapeutic agent into a patient, the automatic portable injection device comprising: a housing (102, 202, 635, 735, 1802, 2002, 2102, 2402, 5102, 5204, 5302, 5404, 5504) comprising a portion of contact with the patient that can be fixed to the patient; an injection assembly disposed mobilely in the housing containing a ^hypodermic injection ^{needle (118,} 218 ^{, 625, 725, 1206, 1306, 1812, 2008, 5202, 5304) for insertion into the patient, the} injection assembly movable between a retracted position in which the injection needle does not protrude outside the housing and an extended position in which the injection needle protrudes outside the housing; a container (106, 206, 605, 705, 1102, 1202, 1302, 1400, 1606, 1706, 2004, 2506, 2804, 2902, 4104, 4602) provided in the housing to contain the therapeutic agent; a plunger (110, 210, 615, 715, 2408, 2508, 2802, 3916) mobilely disposed in the container to expel the therapeutic agent from the container in the injection assembly; a plunger drive mechanism (112, 212, 630, 730, 2406, 2510, 3900, 4000) to drive the plunger using a mechanical or hydraulic mechanism inside the vessel; a retraction activator (5312, 5314) sensitive to a change of state of the portable automatic injection device from an injection state to a post-injection state, in which the portable automatic injection device enters the post-injection state after the administration of a therapeutically effective dose of the therapeutic agent is completed and enters the post-injection state after the withdrawal of the portable automatic injection device from the patient before the end of the administration of the therapeutically effective dose of the therapeutic agent; Y a retraction mechanism (4810) for automatically retracting the injection assembly from the extended position in the injection state to the retracted position in the post-injection state after activation by the retraction activator. 2. The portable automatic injection device of claim 1, wherein the container comprises a syringe, the syringe comprising: a cylinder portion (106, 1102, 1202, 1302, 1400, 1606, 1706, 2506, 2804, 3902, 4104) to contain the therapeutic agent; Y a syringe needle (120, 1304, 1402, 1604, 1704, 3904) coupled to a distal end of the cylinder portion to establish fluid communication between the cylinder portion of the syringe and the injection needle (118, 1306). 3. The automatic portable injection device of claim 2, wherein the injection assembly comprises: a partition (114, 1408, 1610, 1811) that is pierceable by the syringe needle (120, 1304, 1402, 1604, 1704, 1808, 2512, 3904) of the syringe; Y a fluid conduit (1406, 1602, 1700) extending between the injection needle and the septum, in which the perforation of the septum by the syringe needle (120, 1402, 1604, 1808) of the syringe couples the portion cylinder (106, 1102, 1202, 1302, 1400, 1606, 1706, 2506, 2804, 3902, 4104) of the syringe and injection needle; wherein the syringe needle (120, 1402, 1604, 1808) of the syringe is separated from the septum (114, 1408, 1610, 1811) when the device is in a pre-injection state, and in which the needle of Syringe (120, 1402, 1604, 1808) punctures the partition (114, 1408, 1610, 1811) when the device is in the injection state. 4. The automatic portable injection device of claim 1, wherein the container comprises a cartridge (610, 710, 2004, 2104), the cartridge comprising: a cylinder portion (206, 605, 705, 1400, 1606, 2004, 4104, 4602) to contain the therapeutic agent; and a partition (1610, 2108) that is pierceable by a piercing needle (220, 1304, 1402, 1604, 2010, 2112). 5. The automatic portable injection device of claim 4, wherein the injection assembly comprises: the piercing needle (220, 1304, 1402, 1604, 2010, 2112) to establish fluid communication between the cylinder portion (206, 605, 705, 1400, 1606, 2004, 4104, 4602) of the cartridge and the injection needle (218, 1306); and a fluid conduit (1502) provided between the injection needle and the piercing needle to establish fluid communication between the injection needle and the cylinder portion of the cartridge; wherein the partition (1610, 2108) of the cartridge (610, 710, 2004, 2104) is separated from the injection needle of the injection assembly when the device is in a pre-injection state, and in which the needle of perforation perforates the septum when the device is in the injection state; Y wherein the perforation of the partition by the injection needle of the injection assembly establishes fluid communication between the cylinder portion of the cartridge and the injection needle. 6 ^{. The portable automatic injection device of claim 1, wherein the container (106, 206, 605, 705,} 1102, 1202, 1302, 1400, 1606, 1706, 2004, 2506, 2804, 2902, 4104, 4602) is mobile inside the housing (102, 202, 635, 735, 1802, 2002, 2102, 2402, 5102, 5204, 5302, 5404, 5504) between a first position in a pre-injection state and a second position in the injection state , in which the automatic portable injection device further comprises a container actuator for automatically actuating the container from the first position to the second position, in which a fluid path is established between the injection needle and the container when the assembly Injection is in the extended position and the container is in the second position in the injection state. 7. The portable automatic injection device of claim 1, wherein the plunger drive mechanism expels the therapeutic agent into the patient at a controlled rate in which a volume of ^{the therapeutic agent ranging from} 0.8 ^{milliliters to} 1 ^{Milliliter is administered by the device for a period} of time ranging from 5 minutes to 30 minutes. 8 ^{. The automatic portable injection device of claim 1, wherein the} plunger ^{drive mechanism} comprises: a snail (2810, 2426); Y a belt (28122442, 2516) that couples the deflection mechanism to the snail and the plunger. ^{9. The automatic portable injection device of claim 8, wherein the} plunger ^{driving mechanism} further comprises: a damping mechanism (2808, 2422, 2520, 3914) coupled to the snail to regulate the movement of the snail; Y a gear train (2420, 2438, 2518, 2814) that includes one or more gears to couple the snail to the damping mechanism. 10. The portable automatic injection device of claim 1, wherein the plunger drive mechanism (3900) comprises: a diversion mechanism (3908); one or more ball bearings (3910) for attaching the plunger deflection mechanism; Y a damping mechanism (3914) coupled to the deflection mechanism and the ball bearings to regulate the movement of the ball bearings. 11. The automatic portable injection device of claim 1, wherein the plunger drive mechanism further comprises: a source (4106) of a working fluid to provide a hydraulic pressure to expel the therapeutic agent from the container; Y a fluid conduit (4110, 4112) provided between the source of the working fluid and the plunger. 12. The portable automatic injection device of claim 11, wherein the plunger drive mechanism further comprises: a damping mechanism (4108) coupled to the container and the source of the working fluid to regulate the expulsion of the therapeutic agent from the container. 13. The portable automatic injection device of claim 12, wherein the damping mechanism comprises a flow limiter (4108) for maintaining the hydraulic pressure downstream of the flow limiter to the vessel at a pressure lower than the pressure hydraulic upstream of the flow limiter to the source of the working fluid, and in which the flow limiter is coupled to the retraction activator and in which the administration of the therapeutic agent in the container causes the flow limiter to activate the retraction activator. 14. The automatic portable injection device of claim 1, further comprising: a needle locking mechanism (4608, 5408, 5508) for automatically locking the injection needle in the retracted position inside the housing in the post state -injection. 15. The automatic portable injection device of claim 14, wherein the needle locking mechanism comprises: a barrier mechanism (5208) disposed mobilely over an opening of the injection needle (5206) in the housing; wherein the opening of the injection needle is open and allows the injection needle (5202) to protrude out of the housing when the barrier mechanism is in a first position; Y wherein the opening of the injection needle closes and prevents the injection needle (5202) protrudes out of the housing when the barrier mechanism is in a second position. 16. The automatic portable injection device of claim 14, wherein the needle locking mechanism comprises: a needle lock release mechanism (5410, 5510) sensitive to the retraction of the injection assembly from the extended position in the injection state to the retraction position in the post injection state; Y a pivoting member (5508) coupled to the injection needle and the needle lock release mechanism; wherein the activation of the needle lock release mechanism causes the pivoting member to pivot the injection needle away from an opening of the injection needle in the housing. 17. The automatic portable injection device of claim 1, wherein the retraction activator (5312, 5314) is activated after the administration of a therapeutically effective dose of the therapeutic agent or after the withdrawal of the automatic portable injection device of the patient before finalizing the administration of a therapeutically effective dose of the therapeutic agent. 18. The portable automatic injection device of claim 1, wherein the therapeutic agent comprises a TNFa inhibitor. 19. The automatic portable injection device of claim 1, wherein the therapeutic agent comprises any of a fusion protein, an enzyme, an antibody, or its antigen-binding fragment in a solution. 20. The automatic portable injection device of claim 1, wherein, after activation by the retraction activator, the retraction mechanism automatically raises an injection button (116, 216, 2006,) containing the needle automatically injection in the injection assembly. 21. The portable automatic injection device of claim 1, wherein the retraction activator is coupled to the plunger drive mechanism or to a sensor foot (132, 232) provided at the bottom of the housing.